On a Friday night in Chicago, mobster Johnny Ross briefly meets his brother, Pete, after fleeing from the Outfit. The next morning SFPD detective Lieutenant Frank Bullitt and his team, Delgetti and Stanton are tasked by Senator Walter Chalmers with guarding Ross over the weekend, until he can be presented as a witness to a Senate subcommittee hearing on organized crime on Monday morning. The detectives are told he is in a cheap hotel on Embarcadero. Delgetti takes the first shift followed by Stanton and then Bullitt. At 1am Sunday, while Stanton is phoning Bullitt to say Chalmers and a friend want to come up, Ross unchains the room door. Two hitmen burst in shooting Stanton in the leg and Ross in the neck.
Chalmers holds Bullitt responsible. Ross dies in hospital from his wounds but Bullitt conceals the death to keep the investigation open, sending the body to the morgue as a John Doe. An informant says that Ross was in town because he stole millions of dollars from the Chicago Outfit. Bullitt also finds out he made a long-distance phone call to a hotel in San Mateo.
While driving his Ford Mustang, Bullitt becomes aware he is being followed by a Dodge Charger driven by the two hitmen. An extended chase ensues through the streets of San Francisco to Brisbane. Eventually the Dodge crashes off the road, killing its occupants in a fiery explosion.
Bullitt and Delgetti are confronted by their boss, Captain Sam Bennett, as well as Chalmers (who is assisted by SFPD Captain Baker). After being served a writ of habeas corpus, Bullitt reveals that Ross has died. Bennett ignores the writ and lets Bullitt investigate the lead of the long-distance phone call to San Mateo. With no car, Bullitt gets a ride from his girlfriend Cathy. At the hotel, Bullitt finds the woman who phoned, garrotted, in her room. Cathy follows the police to the crime scene and is horrified. On the way back to San Francisco she confronts Bullitt about his work, saying “Frank, you are living in a sewer”. She wonders, “What will happen to us?”
While examining the victim’s luggage, Bullitt and Delgetti discover a travel brochure for Rome and traveler’s checks made out to an Albert and Dorothy Renick. Bullitt requests their passport applications from Chicago. Bullitt, Captain Bennett, Chalmers and Captain Baker gather around the telecopier as the applications arrive. It turns out Chalmers sent Bullitt to guard a doppelgänger, Albert Renick, a used car salesman from Chicago, while his wife Dorothy was staying in San Mateo. Bullitt realises that Ross was playing the politically-ambitious Chalmers by using Renick as a decoy so he could slip out of the country Sunday night.
Delgetti and Bullitt watch the Rome gate at San Francisco International Airport, however, the real Ross (on Renick’s passport) has switched to an earlier London flight with his ticket for Rome. Bullitt boards the plane after it is ordered to return to the terminal but the mobster escapes through the rear cabin door. In the crowded passenger terminal, Ross kills a deputy sheriff before being shot dead by Bullitt. Chalmers arrives to survey the scene, but leaves saying nothing. Bullitt arrives home early on Monday morning to find Cathy, who, having chosen to stay, is asleep in his bed.