Richard Kimble (Harrison Ford) is a successful , University of Chicago-trained, Chicago based vascular surgeon who returns home from an operation after a party one evening to find his wife (Sela Ward) dying following a brutal attack and a mysterious one-armed man with a prosthetic arm escaping. Despite his attempts to save her and his testimony about the one-armed man, Kimble is convicted of first-degree murder, due to evidence such as a misunderstood 9-1-1 call, his fingerprints found "on the lamp, the gun, and the bullets," and no signs of forced entry by the one-armed man. Kimble is sentenced to life in prison.During the bus ride to the prison, one of the prisoners fakes a seizure and begins to foam at the mouth as if poisoned. A guard unlocks the cage separating him from the prisoner to assist him. The prisoner stabs him with a shank made from a concealed sharpened toothbrush, and chaos ensues. Another guard shoots the prisoner with a shotgun. A second prisoner tries to grab the gun from the guard, but in the struggle, the gun goes off and kills the driver. The bus crashes through a guardrail, rolls down a hill, and lands on a railroad track. The light from an approaching freight train appears, and Kimble manages to pull himself and one of the guards to safety just as the train rams into the bus at speed. The bus is dragged on the front of the first locomotive for several hundred feet, but upon crossing a trestle, the first locomotive's coupler breaks, and every car from the second engine on back derails. Kimble manages to outrun the derailing locomotive as it buries itself nose-first in the ditch.Kimble is freed from his chains by another survivor, Copeland, and both escape from the scene on foot.A car arrives at the crash site, containing Deputy United States Marshal Samuel Gerard (Tommy Lee Jones), who leads a team of men from the US Marshals Service Fugitive Task Force, including Marshals Cosmo Renfro (Joe Pantoliano), Bobby Biggs (Daniel Roebuck), Erin Poole (L. Scott Caldwell), and Noah Newman (Tom Wood). They observe the debris, and Gerard finds the local sheriff, Rollins, interviewing the old guard who survived the wreck with minor injuries. The guard, given the suddenness of the wreck, is under the impression that all of the prisoners were killed in the wreck, and takes credit for Kimble's actions (getting the other guard out of the bus). Gerard requests for Rollins to establish police checkpoints, which Rollins is skeptical of doing until Gerard requests to have jurisdiction passed over to him. Just then, Cosmo recovers a pair of unshackled leg irons, and a manhunt begins for Kimble.The next morning, as the Marshals watch the cleanup work, the younger guard (the one who was wounded in the revolt), after being trapped for more than twelve hours underneath debris from one of the locomotives, is extricated, alive.There are many close calls where Kimble almost gets captured, mostly brought on by Kimble's compassionate instincts as a doctor. The first instance is at a hospital after Kimble shaves off his beard, and changes into a doctor's uniform. He very easily avoids being detected by a state trooper at the hospital on the lookout for him. He also happens to be present when the ambulance containing the wounded guard arrives. He helps the paramedics unfold the wheels on the gurney. The guard recognizes Kimble, but Kimble quietly puts the guard's breathing mask down to keep him quiet, and gives the paramedics a detailed description of the guard's likely injuries, which astonishes the paramedics. As soon as they leave, Kimble steals their ambulance.Kimble is first discovered when he uses his lights and siren going through a grade crossing. He is pursued by the Illinois State Police on land and by Gerard in a helicopter running alongside the highway. Kimble is forced to a halt by a police road block in a tunnel near a dam. He exits the ambulance and is pursued by Gerard through the dam's drainage system. At one point, Kimble confronts Gerard and insists on his innocence. Gerard, whose mission is simply to capture Kimble and not to solve the crime, tells him "I don't care!" Kimble tries to continue running but Gerard eventually traps him near the end of a spillway. Kimble escapes by doing a Peter Pan (backflip) off the dam into the water below.The encounter with Gerard at the dam makes Kimble realize that the authorities will always accept his guilt as a matter of fact, and that the only way to ever recover his freedom is by finding the real killer. The fact that Kimble pointed a gun at Gerard during this encounter gives Gerard a strong motive to pursue his fugitive vigorously. Kimble makes his way through the woods, and eventually dyes his hair to conceal himself more easily on his way to a truck stop. As he walks down the road, a woman picks him up and offers him a ride. Kimble accepts.We next cut back to the Marshals office in Chicago, where Gerard is told by Cosmo that they've found "him" shacked up with some babe in the suburb of Whiting. Poole notes that "she" left work that night and took him home, and Biggs reports that "her" car has been spotted outside her house. Gerard asks Cosmo if they can borrow his cousin's truck.We cut to a suburban Chicago neighborhood. It is a quiet, cold, morning. We notice a homeless woman walking across the street with a shopping cart while trying to keep warm. A garbage truck is seen making trash pickups, and a plumber is seen climbing out of his van, preparing for a job, and two dishevelled drunks are walking across the lawn, heading towards a small brick house. However, on closer look, we realize that all of these people are actually Marshals in disguise: the "homeless woman" is Poole, the "drunks" are Gerard and Newman, the "plumber" is Cosmo, and the "garbagemen" are Deputies Biggs and Henry (Johnny Lee Davenport). As they advance on the house, flanking it from all sides, the men quietly check their weapons. Gerard and Newman lead the raid on the house, arousing the residents. As the deputies clear out each room in the house, Newman is suddenly grabbed by Copeland, the other escapee who survived the train crash (the hideout is his girlfriend's house). Copeland takes Newman hostage with his own weapon, and threatens to kill him unless he is given a car. Gerard follows Copeland's voice, and before Copeland can kill Newman, Gerard shoots him twice from point blank range with his Glock 17. He then quickly has to get Biggs and Henry, who burst in at the sound of gunshots, to stand down. Later, as the police mop up, when Newman (who temporarily lost hearing in one of his ears) asks Gerard why he didn't try to reason with Copeland, Gerard whispers to him, "I don't bargain."After being reprimanded by his boss for killing Copeland (who was wanted for interrogation), Gerard and his men listen in on a wiretapped conversation between Kimble and his lawyer, in which Kimble's lawyer tells him to turn himself in. They can make out the sounds of an elevated train rumbling by overhead. Further enhancement reveals bells from a drawbridge and a P.A. announcer on board an 'L' train saying, "Next Stop: Merchandise Mart," which tells Gerard that Kimble is back in Chicago.Kimble returns to Chicago to search for the one-armed man who shot Helen, believing that the guy might still be in Chicago. Kimble also makes contact with many of his former medical friends and associates, virtually all of whom have never believed Kimble to be guilty and are more than willing to help him. He also meets his close friend Dr. Charles Nichols (Jeroen Krabbé), who gives Kimble money, becomes a contact for him, and offers to help in any way. Later, when confronted by Gerard, Dr. Nichols boldly tells him to give up because Kimble is too smart to ever be captured.Kimble rents a basement apartment and makes fake ID cards to pose as a janitor to get access to Cook County Hospital, where he searches the computers in the prosthetic limb area for patient information matching the description of the one-armed man.Unfortunately, one of the people Kimble has chosen to stay with include a drug dealer. He only finds out this when he wakes up one morning after having a nightmare about Helen's murder. As he wakes up, he hears a series of car doors slamming out front. He looks out.... and sees the police running towards the house! A few of the officers break down the front door of the house while tactical assault officers circle the house, looking to cut off escape routes. Curiously, none of them head for the basement. Kimble then hears footsteps above, as the dealer and his accomplice upstairs try to break for it. They burst out a back door, run down the steps to the yard, where the police arrest them, handcuff them, and lead them away.The drug dealer informs police that Kimble is living with them. While Gerard arrives at the apartment, Kimble is confronted at the hospital by a doctor (Julianne Moore) who had seen him change a recently admitted boy's medical orders so that he could have a life-saving heart operation, but Kimble manages to escape. Gerard, always in hot pursuit, arrives with the police and wonders why someone as smart as Kimble would risk capture by going to such a high-profile place as a hospital. At that moment, Gerard sees a one-armed man walk by and realizes what Kimble was probably up to.Going through the list of men with prosthetic limbs, Kimble discovers that one is in jail for armed robbery. He visits this man but sees that it is not his wife's murderer. Trying to understand Kimble's movements, Gerard also found that same man on a list of one-armed men with criminal records. Gerard arrives shortly after Kimble, giving him a close call when they pass on the stairs, but he manages to escape into the Saint Patrick's Day parade, donning a hat to disguise himself.Kimble next checks on another name on the list: Frederick Sykes. When he is unable to reach Sykes by phone, Kimble breaks into Sykes' residence. In the apartment, Kimble finds a prosthetic arm similar to the one he remembered on the killer. He also finds some photos, one of which shows Sykes with another doctor who he met at the fundraiser, Dr. Alec Lentz, who was a key doctor behind the push for the drug Provasic. Then Kimble finds a timecard showing that Sykes works at a pharmaceutical company called Devlin-McGregor. He remembers that Devlin-McGregor sponsored the fundraiser he was attending on the night Helen was killed, which causes Kimble to realize that he was the intended target of the killer.Kimble then places a call to the Marshal's office, but leaves the phone off the hook after conversing with Gerard. Gerard and his men trace the call to Sykes' apartment, and conduct a search of the place. Eventually, Sykes returns home, and Gerard questions him. Gerard learns that Sykes is a security guard for Devlin-McGregor, handling security for their top executives. Sykes professes his innocence, stating that 15 others can vouch for his presence out of town, as he had told the police when they first questioned him about Helen's murder.Gerard, however, is skeptical of Sykes, and sets up surveillance outside his residence. Gerard also is aware of the photo that Kimble was looking at, due to fingerprinting of the apartment, and assigns Newman and Biggs to check out the identity of Lentz in the photo.After he leaves Syke's apartment, Kimble calls Nichols, claiming that he now knows who was behind his wife's murder. Kimble is sure that the murder was planned by Lentz as a way to keep him quiet: Kimble had been seeing an increase in the number of patients in the research program for Provasic, a new wonder drug, being admitted to him with damaged livers (including the patient Kimble had been called to operate on the night of the murder). Nichols explains to Kimble that this might not hold up, as Lentz is dead: he died in a car accident the previous year. Kimble is still wanting to double-check his findings, and asks Nichols to call a hospital associate of theirs to look over the samples.Shortly after this, Gerard and several of his men meet with Nichols, questioning him about Sykes and the photo. Nichols claims he doesn't recognize Sykes or one of the men in the picture that Gerard is keen to know about. Returning to their headquarters, Newman explains that in digging deeper, he found that on a blowup of the picture of Sykes and Lentz, Lentz is wearing a shirt that mentions 'Chicago Memorial Hospital,' and goes there to investigate.Newman and another marshal go to the hospital, also learning Dr. Lentz's identity. One person whom they are referred to is a man in the hospital named Bones Roosevelt (John M. Watson Sr). When they mention Dr. Kimble, Roosevelt grows uneasy, before finally admitting that he had seen Kimble previously, when Kimble came by to pick up some samples. Upon further investigation, they find out that Kimble had just been to see Bones about some tissue samples. Bonesalso answers some questions regarding Lentz. It actually turns out that Lentz was Dr. Nichol's boss! This revelation is relayed to Gerard, who wants to now bring Nichols in, on the basis that he lied regarding their investigation, and also intends to bring Sykes in as well.Meanwhile, Kimble has taken the tissue samples to former associate, Dr. Kathy Wahlund (Jane Lynch). Checking the samples, they see that they have been tampered with, and they all came from the same healthy liver. Kimble asserts his theory that it was Lentz, but Dr. Wahlund notes that half of the samples that he approved were done so on the day he died, thinking someone with access to Lentz may have been behind this. Kimble immediately suspects Dr. Nichols, and goes to confront him.Kimble takes an elevated train to a hotel where Nichols is giving a speech that night as keynote speaker at a medical conference. On the train, he encounters Sykes (who had been trailing him from the hospital, on Nichols' orders, and had escaped from the cops by calling the fire department and walking away in the chaos). Their confrontation is interrupted by an officer who pulls his gun on Kimble. Sykes shoots and kills the cop. Kimble uses the distraction, and manages to subdue Sykes, and handcuffs him to a pole on the train. Pulling the emergency brake as the train comes into the Clark/Lake station, Kimble breaks a window, and escapes from the train on foot. Several witnesses notice Kimble heading towards a hotel, and this is radioed to the CPD and to Gerard. Of concern to Gerard is that word of an 'officer down' has made Kimble a dangerous suspect in the eyes of the Chicago Police, who will most likely take him down as soon as they can.Kimble manages to get to the conference room in the hotel, where Nichols is giving a speech in regards to the pending approval of the Provasic drug. Nichols attempts to usher Kimble quietly into a small suite off to the side of the conference room, but Kimble vocally accuses Nichols regarding his motive: Dr. Nichols falsified his research, and most likely killed Lentz.Once in the suite, Nichols attacks Kimble, and the two scuffle in the room, before it eventually spills out onto the hotel's rooftop.Gerard arrives but is told to stay out of the situation by the CPD. Gerard storms past the CPD and his Marshals eventually find where Kimble went. Gerard makes his way to the rooftop. Gerard watches as Kimble and Nichols fight, before plummeting through a skylight, and fall atop an elevator that then descends.The chase eventually leads them to the hotel's laundry. Nichols recovers from the fall first, but Kimble is soon behind him. Gerard eventually makes it to the floor, yelling out to Kimble, claiming he knows of the Doctor's innocence, as well as what really happened: on the night of his wife's murder, Nichols had the keys to Kimble's house, which was how Sykes got in without forced entry. Nichols also telephoned Sykes from Kimble's car. Nichols manages to knock out Renfro and takes his gun, and is about to shoot Gerard when Kimble disarms him.In the aftermath, Sykes and Nichols are taken into custody, and Gerard escorts Kimble out of the hotel in handcuffs. In the back of their car, Gerard removes the handcuffs, and gives Kimball a small bag of ice for his bruised hands."I thought you didn't care," says Kimble."I don't," jokes Gerard.With that last exchange, the car pulls away, and the audience is confident that Kimble's name is now cleared.