Wyatt (Peter Fonda) and Billy (Dennis Hopper) are freewheeling motorcyclists. After smuggling cocaine from Mexico to Los Angeles, they sell their haul and receive a large sum of money. With the cash stuffed into a plastic tube hidden inside the Stars & Stripes-painted fuel tank of Wyatt's California-style chopper, they ride eastward aiming to reach New Orleans, Louisiana, in time for the Mardi Gras festival.
During their trip, Wyatt and Billy stop to repair one of the bikes at a farmstead in Arizona and have a meal with the farmer and his family. Later, Wyatt picks up a hippie hitch-hiker, and he invites them to visit his commune, where they stay for the rest of the day. The notion of "free love" appears to be practiced, with two of the women, Lisa and Sarah, seemingly sharing the affections of the hitch-hiking commune member before turning their attention to Wyatt and Billy. As the bikers leave, the hitch-hiker gives Wyatt some LSD for him to share with "the right people".
Later, while riding along with a parade in New Mexico, the pair are arrested for "parading without a permit" and thrown in jail. There, they befriend ACLU lawyer George Hanson (Jack Nicholson), who has spent the night in jail after overindulging in alcohol. George helps them get out of jail and decides to travel with Wyatt and Billy to New Orleans. As they camp that night, Wyatt and Billy introduce George to marijuana. As an alcoholic and a "square", George is reluctant to try it due to his fear of becoming "hooked" and it leading to worse drugs but quickly relents.
Stopping to eat at a small-town Louisiana diner, the trio attracts the attention of the locals. The girls in the restaurant think they are exciting, but the local men and a police officer make denigrating comments and taunts. Wyatt, Billy, and George decide to leave without any fuss. They make camp outside town. In the middle of the night, a group of locals attack the sleeping trio, beating them with clubs. Billy screams and brandishes a knife, and the attackers leave. Wyatt and Billy suffer minor injuries, but George has been bludgeoned to death. Wyatt and Billy wrap George's body in his sleeping bag, gather his belongings, and vow to return the items to his family.
They continue to New Orleans and find a brothel George had told them about. Taking prostitutes Karen and Mary with them, Wyatt and Billy wander the parade-filled streets of the Mardi Gras celebration. They end up in a French Quarter cemetery, where all four ingest the LSD the hitch-hiker had given to Wyatt and experience a bad trip.
The next morning, as they are overtaken on a two-lane country road by two local men in an older pickup truck, the passenger in the truck reaches for a shotgun, saying he will scare them. As they pass Billy, the passenger fires, and Billy has a lowside crash. The truck passes Wyatt who has stopped, and Wyatt rides back to Billy, finding him lying flat on the side of the road and covered in blood. Wyatt tells Billy he's going to get help and covers Billy's wound with his own leather jacket. Wyatt then rides down the road toward the pickup as it makes a U-turn. Passing in the opposite direction, the passenger fires the shotgun again, this time through the driver's-side window. Wyatt's riderless motorcycle flies through the air and comes apart before landing and becoming engulfed in flames.