In the mid-19th century, the Five Points district of New York City is a melting pot of different ethnic groups, with each vying for power and control. The film follows the story of Amsterdam Vallon, a young Irish-American who returns to the Five Points to avenge the death of his father, the former leader of the Dead Rabbits gang, who was killed years earlier by Bill 'The Butcher' Cutting, the ruthless and xenophobic leader of the native-born American gang, the Natives. Amsterdam's quest for vengeance becomes complicated as he infiltrates Bill's inner circle, playing a long game to earn the murderer's trust and plot his downfall.

Meanwhile, as Amsterdam becomes increasingly entangled in the local politics and power struggles of the Five Points, he meets and becomes romantically involved with Jenny Everdeane, a skilled pickpocket with connections to his past and a complicated history with Bill. The city is on the brink of the Civil War, with the draft riots looming, and anti-immigrant sentiment on the rise, creating a backdrop of political and social turmoil that further complicates Amsterdam's mission. His personal vendetta against Bill becomes entwined with the larger battles for dominance among the gangs and the struggle of the Irish immigrants to carve out a place for themselves in the harsh landscape of the American urban ghetto.