The film opens with Priest Vallon (Liam Nesson) shaving with an old, rusted straight razor. He deliberately cuts his cheek and then hands the blade to his son Amsterdam, who is about to wipe off the blood. Vallon tells him to leave it there, and his son puts away the blade in a black pouch with a sliver cross clasp (important later). He then says a prayer to St. Michael, puts a medallion over Amsterdam's head, grabs a steel cross, and marches out of his cave with Amsterdam. They walk past people making and finishing their weapons, including a woman with clawed gloves named Hellcat Maggie. Vallon, his son, and the rest take communion as they continue exiting the caves. They finally reach the top level of an old brewery. They stop and Vallon asks a man named Monk if he will join them. Monk says he'll fight for pay. Vallon promises him ten dollars, so Monk agrees, picks up his wooden club, and kicks open the door, revealing a snow-covered intersection known as Paradise Square.
Vallon and his crew, aka the Dead Rabbits, leave the brewery and make their way onto the street. Amsterdam runs to join children on the steps of a nearby building, while the Dead Rabbits await the arrival of the Natives. A few moments later, men dressed in blue, led by Bill the Butcher (Daniel Day-Lewis), a ruthless New Yorker with a glass eye, walk onto the street, clearly outnumbering the Rabbits. Bill says that the ensuing fight will decide who holds the rule of the Five Points; Bill's mob who are Protestant or Vallon's Catholics. Vallon recants that it's a free country, that he and is immigrant crowd have been harassed by Bill and his men. The Rabbits are then joined by several other gangs that have allied themselves with Vallon, greatly increasing their numbers.
Moments later, they begin fighting. Monk is mashing people in the head, Maggie is biting a man's ear off, and people's legs are getting broken while others are being stabbed, slashed and bludgeoned. Bill and Vallon slowly make their way towards each other, but as Vallon draws near Bill directs one of his men to attack Vallon. Vallon kills the man, but is stabbed by Bill in the process. Vallon tries to fight back, but is stabbed in the side. Vallon falls to the ground, and a horn is blown. All of the men stop fighting and stand around the dying Vallon. Amsterdam pushes his way to his father's side. Bill makes a speech about how all the fighting is done and how he has slain Vallon. Vallon looks at his son, tells him to always stay focused and then asks Bill to finish him, which Bill obliges, leaving the knife on Vallon's chest. Bill says that Vallon may not be touched so that he may reach Heaven with honor. Monk tells him to wait, goes over to Vallon's body and presumably takes the money he's owed from his pocket, and then offers Amsterdam his condolences. As they haul Vallon away, Bill's men ask what they should do with the boy. He tells them to put him in a school so he could get an education. Amsterdam quickly grabs the knife from his father's chest, threatens Bill's men, and runs inside the brewery. As the men chase him, a boy hits one of them in the shin, causing him to fall. Amsterdam runs down to his cave, opens a secret compartment in the ground, and places the medallion and dagger inside. Bill's men grab him. Outside, Priest's body is placed on a cart and wheeled reverently out of the square. As we zoom out of the area, we see that the battle took place in the Five Points area of Lower Manhattan and the year is 1846.
Sixteen years pass and Amsterdam (Leonardo DiCaprio) is being given a blessing and a Bible by a priest. He is still in New York but in an orphanage, Hell Gate, on a nearby island. As he leaves, he looks at an Asian man, walks over a bridge, and tosses the Bible in the river.
Amsterdam narrates that during the Civil War, New York was a "city of tribes", rival gangs competing for control of the Five Points and beyond. Bill the Butcher is walking through a hallway of Tammany Hall to the office of Boss Tweed (Jim Broadbent), who is running for some sort of political office. Tweed is discussing how they can get more voters and social and municipal services for the poor in the city. Then it cuts to Amsterdam walking on the docks as more Irish are disembarking a ship. The immigrants are harassed openly by Bill's men, particularly an old woman who is hit in the face by something one of Bill's men throws and is yelling for her to get back on the boat. She falls to the floor, and is helped up by a gentleman and some children.
Amsterdam passes them by and is greeted by a man who welcomes him (mistaking him for an immigrant), offers him bread, and reminds him to vote for Tweed. Amsterdam is also asked to draft in the army, but refuses. Other Irish are offered money, three meals a day, and luxuries for their families if they join right away and ship out immediately. They agree, register, change, and board a boat.
Amsterdam makes his way to his cave and opens the compartment. He takes out the dagger and the medallion. He is interrupted by Johnny Sirocco (Henry Thomas) and Jimmy Spoils (Larry Gilliard Jr.) as he says a prayer. They tell him to give them his possessions, and when he refuses, Jimmy tries to attack him, but Amsterdam knocks him over and almost breaks his nose. Johnny pulls out a knife, which Amsterdam turns against him. Johnny notices the medallion. Amsterdam leaves the cave and goes out to the street. Johnny follows him and asks if he's the priest's son. Amsterdam answers yes, and Johnny begins to update him on the Five Points. He tells him how Maggie tried to open a pub, but drank herself out of business; how Monk owns a barber shop; and how Bill celebrates Priest Vallon's death every year by drinking a glass of alcohol he's lit on fire.
Johnny is then bumped into by Jenny Everdeane (Cameron Diaz). He introduces her to Amsterdam. When she comments to them that they are terrible at conversation, Amsterdam recants that they are deep thinkers. She wishes them a good day and hopes the God shines on them and joins her friends. Johnny swears that Jenny likes him, but Amsterdam informs him that she stole his watch. Johnny searches his pockets, looks up, and tries to make it seem like it happens often.
Later that night, a house is on fire. The sirens of Tweeds firemen can be heard closing in. A man covers a fire hydrant with a barrel and sits on it. Tweeds men come and he uses the incident to campaign on the street. Another group of firemen arrive, led by the Butcher and the two groups start to fight. Johnny takes advantage, grabs Amsterdam, and enters the burning building in search of valuables. Amsterdam finds watches, while Johnny becomes mesmerized by a music box. A beam falls and traps him in. He calls for Amsterdam, who grabs more jewelry and heads out. He returns, jumps over the beam with a blanket, grabs Johnny, and helps him out of the house. Just as they are leaving, Bills men come, the barrel is removed from the hydrant, and they begin to put out the fire.
Johnny then takes Amsterdam to meet his friends Fuzzy, Jimmy, and some others. There they show everything they stole from the burning building until Happy Jack (John C. Reilly) arrives. He was one of the Dead Rabbits who's now a crooked police officer. He takes a few pieces in tribute to himself and leaves.
The next day, Amsterdam and Johnny then take the rest to a pub/brothel, where Bill plays cards. Johnny walks up to Bill to give him the money, but Amsterdam stays further back. He notices a drawing of his father on the wall. Bill asks Amsterdam what his name is. Amsterdam replies. Bill then calls himself New York, and tells Johnny how they can make more money.
Later that night, Fuzzy, Jimmy, Amsterdam, and Johnny are rowing through the harbor until they reach a ship. When they board it, they find that it has already been robbed. They continue to search for anything that might have been left until Amsterdam notices a man dressed in a Union uniform coming out with a rifle. He warns Jimmy and everyone else to hit the deck. A shot is fired, but only into the air because the man was dying. The man falls forward to reveal a knife in his back. Everyone is in the rowboat waiting when a body falls inside it. Its the Union soldier. Amsterdam threw it in and he then jumps into the boat. He is then shown trading the body for money. The headline in the newspaper reads something about a gang who sells bodies to science, calling them "ghouls". Bill applauds Amsterdam's quick thinking, but his right hand man, Mr. McGloin doesn't agree. They begin calling each other names and eventually begin fighting. Amsterdam is clearly winning when the fight is broken up. During the scuffle, the drawing of Priest Vallon fell to the ground. Bill picks it up, looks at it, and puts it back on the wall. He then takes Amsterdam and Johnny on a tour of the Five Points as Happy Jack is giving a rich family a tour. Monk also walks by greets Bill, and pushes up Amsterdam's hat to get a look at Amsterdam's face.
Amsterdam comes across Jenny again and she bumps into him. He immediately begins checking his pockets, but realizes too late that she took his medallion. He follows her onto a street car. He sees her brilliantly steal a man's pocket watch, and then follows her to the home of a wealthy family where she poses as a maid and slyly robs them as well. When she's done, he yanks her aside and demands his medallion. She threatens him with a knife and cuts him on his neck slightly before he takes it from her. She then opens her blouse and shows him all the medallions shes got. He takes his, returns her dagger, and begins walking with her.
Jenny and Johnny attend a public dance. Jenny is seated with her back to the men and is holding a mirror. She passes up three men, including Johnny, before choosing Amsterdam. They begin dancing, and later go to the docks where they are about to have sex. She mentions Bill and he wonders what she gives him in return. When he realizes, he gets up and leaves.
Amsterdam then begins working for Bill. He is even shown by Bill how to hurt or kill people by stabbing them in certain areas. Bill also makes Amsterdam, Fuzzy, Jimmy, and Johnny boxing bet collectors. When a boxing match is broken up by the police, Amsterdam finds a place where the police cannot break it up. Bill gives him all the glory, but his joy is interrupted when he sees Jenny leave with Johnny.
At a theatre showing of Uncle Tom's Cabin, the audience begins throwing vegetables at the stage. An assassin uses this to try to kill Bill. Amsterdam notices, warns Bill, and tackles the guy to the ground, but not before he gets a shot off. He shoots Bill in the shoulder. Bill's men shoot him in return. Bill then tortures the man, demanding to know who sent him, but the man dies before he can answer. Amsterdam then runs off and begins crying. Monk finds him, and tells him that his father tried helping the Irish, not the Natives. Amsterdam reminds Monk of taking money from Priest Vallon when he died. Monk then hands him the black cloth with the cross clasp, and says he took it for safe-keeping.
Later that night, Bill, Amsterdam, Tweed, and others are drinking in the brothel. Jenny comes by and cleans Bills wound then goes upstairs to her room. Amsterdam angrily follows her and grabs her. She tells him she'll bite him if he tries to kiss her. She lunges a few times, and they eventually kiss and sleep together. Johnny witnesses this and runs off.
Amsterdam awakes to find Bill watching him, sitting in a chair and draped in an American flag. He asks Bill if it was okay that he slept with Jenny. Bill says he doesn't mind. Bill then begins talking about how Priest Vallon spared his life, and how Bill removed his own eye, the one that looked away in shame, and sent it to Vallon. He then describes the day he killed Vallon. Bill speaks of how he's gained his power in the Five Points through "the spectacle of fearsome acts" and how "civilization is crumbling." Bill then leaves.
Amsterdam tells Jenny if she wants to know anything about him, she should ask. She explains how Bill took her in and how he never put his hands on her until she told him to. Later that night, Monk sees Amsterdam throwing a dagger into a block of wood. It's as if Amsterdam were practicing for something.
Johnny is then seen talking to Bill. He tells Bill about Amsterdam being Vallon's son. Bill reacts violently, nearly killing Johnny, but he listens. Meanwhile, Amsterdam is seen walking into an Asian-themed restaurant. He tries to call Johnny as he walks to his table, but Johnny pays no mind. He sits, and Jenny comes to him. An announcer then comes and begs Bill to perform with his daggers in a piece called "The Butcher's Apprentice". He asks for Jenny to participate. She steps onto the stage and Bill begins throwing knives, his throws become increasingly dangerous until he is seriously scaring her -- one shot even cuts her neck. He then walks to his table, says some words about Vallon, and lifts up his drink of fire. Amsterdam then throws a dagger at Bill, who blocks the blow with a cleaver and counters with his own throw; his knife embeds itself in Amsterdam's midsection. Amsterdam is held down on a table as Bill headbutts him several times. Bill then declares that Amsterdam will be branded and thrown into the street for everyone to gawk at. He uses a hot knife to burn Amsterdam's cheek while Jenny screams.
Jenny then takes Amsterdam away to a cave where she nurses him back to health. She talks of them leaving and going to San Francisco. Monk visits them and gives Amsterdam Priest's straight razor. When he recovers, he hangs a dead rabbit in Paradise Square. Bill sends Happy Jack to kill Amsterdam, but Amsterdam kills Jack instead and finds sanctuary in the church. Amsterdam hangs Jack's body in Paradise Square where Bill laments the the loss of an easily corruptible cop. Jimmy tells Bill where to find Amsterdam, however, since Amsterdam is hiding in the church, Bill is reluctant to go there and confront him. However, Bill, sensing that Jimmy might betray anyone as easily as he betrayed Amsterdam, has Jimmy impaled on the spiked fence in Paradise Square and left for Amsterdam to find him. When Jenny and Amsterdam find Jimmy, Jenny gives Amsterdam her pistol to mercifully kill his friend.
Amsterdam and his men, now dressed in the red of the Dead Rabbits, are gathering strength, even to the point where Tweed asks for their help in getting votes. He makes a deal with them to allow them to have an Irish sheriff and he will get all Irish votes. They choose Monk, who wins. Bill challenges Monk outside his barber shop. When Monk suggests they go inside and talk like men, Bill throws a cleaver into Monk's back. He then takes Monk's club (which has 44 carvings on it to mark how many people Monk has killed), carves a new notch into it, and clubs Monk with it, finishing him off. At Monk's funeral, Amsterdam quietly challenges Bill to a gang brawl. They later meet and discuss the terms: weapons are permitted, but guns will not be.
The day arrives and Amsterdam cuts himself on the cheek as his father had done. He looks at Jenny, who tells him that she's leaving for San Francisco today with or without him. He tells her it will be over tomorrow, but she leaves.
A conscription act for the Union Army is enforced; anyone who can pay $300 will not be forced to join the army and fight the Confederacy in the Southern states. A series of riots break out, and crowds start pillaging the streets, burning homes, letting the animals at PT Barnum's House of Wonders loose and cutting the telegraph lines so the police and authorities cannot communicate to stop the rioters. Jenny and Jimmy are even attacked in the process. In Paradise Square, the Dead Rabbits and Bill's Natives meet. They are just about to begin brawling when the Navy fires their cannons into the Square killing many members of both gangs. The Army also moves in and fires upon the survivors. In the confusion, McGloin is killed.
Only Amsterdam and Bill are left to fight. Bill uses the thick smoke from the cannon shots to rush Amsterdam and slash him twice. Another cannon shot knocks Bill and Amsterdam to the ground. Bill pulls a piece of shrapnel from his midsection and says he'll die "a true American." Amsterdam takes this opportunity and stabs and kills Bill. Jenny finds him and, that night, they mourn all the friends they lost in the draft riots. Tweed is only upset because he lost so many votes.
Bill is buried next to Priest Vallon in a Brooklyn cemetery that looks out on the Manhattan skyline. Amsterdam is there with Jenny and he buries his father's straight razor on top of Priest's grave. Amsterdam remarks in voiceover that a city like New York will continue to grow and he and his friends and enemies might never be remembered. Decades begin to pass, showing the growth of the Manhattan skyline, ending on the twin towers of the World Trade Center.