Dr. Richard Kimble (David Janssen), falsely accused of murdering his wife, escapes custody while en route to death row and must elude police and Lt. Philip Gerard (Barry Morse), who is consumed with his capture. Kimble must perpetually relocate and change his name while he continues his mission to find the real killer, a one-armed man (Bill Raisch) he saw leave the scene of the crime.

The Fugitive debuted on September 17, 1963 and was an immediate hit. It is widely believed that the character of Dr. Richard Kimble was based on Dr. Sam Sheppard, a young Cleveland, Ohio doctor convicted of killing his wife Marilyn in 1954, despite his claims of a "bushy haired intruder." Sheppard served ten years in prison and was declared a free man by the U.S. Supreme Court on June 6, 1968. "The massive, pervasive and prejudicial publicity attending petitioner's prosecution prevented him from receiving a fair trial consistent with the Due Process Clause of the 14th Amendment." When asked whether The Fugitive was based on the Sheppard case, series creator Roy Huggins said, "I don't care whether people say The Fugitive was based on the Sheppard case. The only reason I deny it is that it happens to be the truth."

Producer Quinn Martin developed several techniques that made The Fugitive different from most television shows on the air at the time. One of them was an introductory narrator (Hank Simms) revealed the desperate state of Dr. Kimble's life with this statement at the beginning of each episode:

Name: Richard Kimble. Profession: doctor of medicine. Destination: death row, state prison. Richard Kimble has been tried and convicted for the murder of his wife. But laws are made by men, carried out by men. And men are imperfect.

Richard Kimble is innocent. Proved guilty, what Richard Kimble could not prove was that moments before discovering his wife's body, he encountered a man running from the vicinity of his home. A man with one arm. A man who has not yet been found.

Richard Kimble ponders his fate as he looks at the world for the last time. And sees only darkness.

Martin also divided the hour long show into a number of acts (Act I, Act II, etc.), the number of "beats" of action per act, and ended each act with a cliffhanger of sorts, ensuring that the audience would come back after the commercial break.