A young African-American orphan is sheltered by a Los Angeles brothel in the 1940s. Working as a towel boy, he is raped by one of the prostitutes. The women name him "Sweet Sweetback" in honor of his sexual prowess and large penis. As an adult, Sweetback performs in the whorehouse sex show.
One night, two white LAPD officers come in to speak to Sweetback's boss, Beetle. A black man has been murdered, and there is pressure from the black community to bring in a suspect. The police suggest arresting Sweetback to appease their superiors, blame him for the crime, and then release him a few days later for lack of evidence. Beetle agrees, and they arrest Sweetback. On the way to the police station, the officers also arrest a young Black Panther named Mu-Mu after some trouble. They handcuff him to Sweetback, but when Mu-Mu insults the officers, they take both men out of the car, undo the handcuff from Mu-Mu, and beat him. In response, Sweetback fashions his handcuffs into brass knuckles and beats the officers, putting them into comas.
Sweetback returns to the whorehouse for help, but Beetle refuses out of fear of being arrested himself. As Sweetback leaves, he is arrested and beaten by order of the police chief, seeking information about Mu-Mu's whereabouts, but escapes when a black revolutionary throws a molotov cocktail at the police car transporting him to the station for more severe interrogation. He next visits an old girlfriend, who similarly refuses him aid but cuts his handcuffs off in exchange for sex. Sweetback then asks his priest for help, but he refuses for fear of the police shutting down the church's drug rehab center.
Police officers interrogate Beetle, seeking to discover Sweetback's whereabouts, rendering him deaf by firing a gun against each ear. Sweetback meets up with Mu-Mu and black gangsters drive them through South Central Los Angeles to the outskirts. Stopping overnight at a seemingly abandoned building, they discover it is a safe house for the Hells Angels. Their helmetted president challenges Sweetback to a duel: asked to decide the weapon and discovering she is a woman, he chooses sex and is judged to win. The bikers leave the men in their club to await a member of the all black East Bay Dragons who will get them to Mexico. During the night, the club is raided by two policemen with drawn guns. Sweetback resists arrest and kills both officers in self-defense, but Mu-Mu is badly wounded. The next morning, the Dragon arrives, but his motorcycle can only carry one; Sweetback asks him to take Mu-Mu, as the activist is their future.
As Sweetback and Mu-Mu continue to evade arrest, pressure mounts on the police; the police chief warns his staff that the fugitives' example could prompt a black uprising. The police badly beat up a black man sleeping with a white woman, believing him to be probably one of the fugitives, and that he deserves a beating in any case. Later, Beetle, now in a wheelchair following the police brutality, is brought to the morgue to identify a body believed to be Sweetback and smiles when he sees it is someone else. As the police trawl black areas for him, they find Sweetback's biological and rather confused mother, who reveals that his birth name is Leroy.
Sweetback pays a hippie to switch clothes with him, deceiving a police helicopter which sends a patrol car in pursuit. Sweetback was also wounded in the shootout and both stows away and hitches rides on trucks and a train heading south. Running through arid country, he survives by drinking from a puddle and eating a lizard. When police hear he might be at a rural hippie musical event, he successfully disguises himself by simulating sex in the bushes. He is later spotted and police borrow a farmer's hunting dogs to track him. Realising he will cross the border before they reach him, a policeman releases the dogs, expecting them to catch and kill him. However, at the Tijuana River, Sweetback stabs the dogs and escapes into Mexico, swearing to return to "collect some dues".
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