Richard Kimble rides into Tucson, Arizona under the name James Lincoln. He checks into a hotel and finds a job as a bartender at the Branding Iron. He meets Monica Welles (Vera Miles), the piano player who escaped from her stalking jealous husband (Ed Welles) played by Brian Keith.

In West Virginia, Kimble arrives at a local coal mining town where he is roughed up by the redneck locals, and then chased by a sheriff's posse. Hiding in the mountains, Kimble meets Cassie, a young woman living in a remote cabin with her grandmother. Cassie tells Kimble she get him to safety because she knows the area, when she is really wanting to keep him around for her own selfish reasons. Meanwhile, Gerard flies to West Virginia after learning from the sheriff that Kimble has been spotted in the area and teams up with the posse to try to find Kimble.

Kimble, working as an apprentice sailmaker in Santa Barbara, California, falls in love with Karen, the daughter of his stern but compassionate boss Lars Christian. But earns scorn from Karen's jealous and overprotective brother Eric. When Lars suffers a heart attack his last wish on his deathbed is to implore Kimble to stay with Karen. Meanwhile, Gerard flies to nearby Los Angeles when he hears about the arrest of a one-armed man for armed robbery and lets the story hit the newspapers, hoping it will flush out Kimble.

After getting into a car accident in a rural Kentucky town, Kimble lands in jail by the redneck sheriff who hates outsiders. But Kimble manages to escape with his cellmate Davey ""Fatso"" Lambert. Hiding out at the Lambert ranch, Kimble sees that Davey's father and brother, Frank, treat the slow-witted Davey badly for blaming him for a barn fire years earlier. Kimble tries to prove Davey's innocence as Gerard flies out to Kentucky after learning of Kimble arrest and forms a posse to track him down.

Kimball is injured while helping save some children from a fiery crash. While recuperating at a local home, he learns that his caretakers are the local sheriff and his wife. As if this weren't bad enough, a news article describing Kimball's heroic deeds goes nationwide. The all-seeing Lt. Gerard reads the article, and then goes to the small town to arrest Kimball.

Kimble returns to his home town in Illinois after learning that his father, John Kimble, has suffered a heart attack and has donated his medical library to the University of Wisconsin and in the process of selling the family house. While Kimble hides out at the home of his sister Donna and her sympathetic husband Leonard, Kimble blames himself for his father's condition, but is more troubled by his younger brother Ray, whom belives Kimble is guilty and thinks he's to blame for ruining his life since people see Ray as ""the brother of a killer."" Meanwhile, Gerard arrives in town to search for Kimble and focuses on Donna and Leonard whom try to shake off the relentless detective long enough for Kimble to get out of town before Gerard finds him.

While working as a warehouse worker, Kimble is recognized by the Greek-born owner, Gus Priamos. Gus tells Kimble that he is dying from cancer and has only six months to live and hopes to aid the Fugitive with a scheme to make it look that Kimble has fled the country to Greece. But when Gus' jealous girlfriend Sophie learns Kimble's idenity through a magazine article, she contacts Gerard whom gets a heads-up on Kimble and Gus' plan.

Kimble answers a classified ad from a certain Ellie Burnett, the daughter of his former defense attorney. They arrange to meet in Kansas City to discuss the information she received about a one-armed man from a private detective hired by her father. But Gerard sees the ad and knows who wrote it because he and Ellie's father were close friends and that Ellie may be in love with Kimble. While Gerard has Ellie investigated, she and Kimble find out that the one-armed man was killed in a fire only a week before. Kimble is devastated, but vows to confirm it. A little later, Ellie's private detective informs her that the one-armed man whom died in a fire was actually in prison at the time of Helen Kimble's murder. But Ellie withholds this news from Kimble and convinces him that they should leave the country, realizing that this may be her only chance at a life with him.

Kimball escapes from his workplace at a hatchery just as Gerard and the local sheriff come to arrest him. As Kimball drives off in the sheriff's car, he discovers that Gerard's son is hiding in the backseat.

On the verge of closing in on the shadowy one-armed man, Kimble is renderd amnesiac after a freak gas explosion at a roadside diner. While the Fugitive fights to regain his memory, a struggle ensues at the local hospital between Margaret Ruskin, a sympathic social worker whom regonizes Kimble and belives him to be innocent, while a local physician, named Dr. Towne, belives Kimble to be guilty. Meanwhile, the one-armed man slips away, but not before he makes an anonymous phone call to the police and Gerard about Kimble's whereabouts.

Kimball takes advantage of a deadly car accident as a way to try and convince Gerard that he is now dead.

On the run from Gerard, Kimball stumbles onto private property belonging to a family of moonshiners. When Gerard gives chase on foot, he too is caught by the backwoods family, and is accused of attacking one of the girls in the family. Kimball has to decide whether or not to keep the family from killing Gerard.