Cullen Bohannon has fallen in with a group of Rebel bandits robbing trains and planning to start a new Confederate colony in Mexico. While attacking Thomas Durant’s payroll train, Cullen is captured by authorities and sentenced to death, but Durant intervenes with a pardon on the condition that Cullen returns to Hell on Wheels to help oversee railroad construction.
Against the advice of Lily Bell, with whom he is now romantically involved, Durant charges Cullen with building a bridge across a river gorge and into sacred Sioux territory.
Sioux attack the nearby town of Durant, NE, causing refugees including Eva and Mr. Toole to return to Hell on Wheels. Eva spurns Elam Ferguson’s attempts to woo her back, upset that he abandoned her to further his career, but forgives him when he avenges the murder of her prostitute friend. Toole is promoted to foreman to take Schmidt’s place after Elam kills him.
Ruth takes over Reverend Cole’s duties and banishes him from the church as he descends deeper into alcoholism. Joseph Black Moon proposes to Ruth, but she declines on the grounds that society would never accept a marriage between an Indian and a white woman. The Swede takes Cole in and sobers him up, encouraging Cole to finish his pro-Indian manifesto.
When Eva tells Elam she’s pregnant with his child, he urges her to abort, worried that Toole would kill her for having a black baby. However, Toole agrees to raise the child even though it belongs to Elam.
A sentry is killed by the Sioux, and the railroad crew refuses to work until they receive protection. After they run reinforcement crew out of town, the men agree to work again, provided the Freedmen act as armed guards.
Cullen’s former gang robs the railroad office, shooting Durant in the process. Cullen and Elam kill the robbers and Durant is transported to Chicago for medical care.
The Swede and Cole secretly distribute rifles to the Sioux. With Sioux warriors at his side, Cole hijacks Durant’s Chicago-bound train and orders Durant to publish Cole’s manifesto. Durant secretly sends word to Lily and Cullen, who convince Joseph to kill Cole and save the hostages.
Lily enlists The Swede to manage the railroad’s finances while Durant is gone. Cullen disapproves, suspecting it was The Swede who armed the Sioux. He imprisons The Swede but is forced to release him due to lack of evidence. The Swede later informs Lily that Durant has been inflating mileage numbers.
Elam hijacks a shipment of whiskey, forcing the Starlight Saloon owner to sell his business to the McGinnes brothers. In return, the brothers give Elam a cut of their profits and a plot of riverfront land. Elam quits the railroad and builds a house for himself, Eva and the baby.
Cullen contemplates leaving town, but stays after Lily chastises him for running from his problems. They make love and start a romantic relationship.
Durant returns from Chicago, addicted to opium and walking with a cane. His wife, Hannah, accompanies him to help oversee railroad business. The Durants invite Cullen and Lily to dinner one night and are impressed by Cullen’s aristocratic background.
As bridge construction nears an end, The Swede sabotages the equipment, causing the death of railroad workers and a setback in progress. When confronted by Durant about construction pace, Cullen blames Durant for overselling mileage to the board in New York. Durant deduces that Lily discovered the mileage shortfall and orders Elam to kill her.
With the bridge complete, Cullen successfully drives the train across the gorge. Durant offers Cullen a partnership in the railroad if he’ll help appease the board back east, but Cullen declines.
Hannah tries to force Lily out of town, giving her a one-way ticket to New York, but Lily steals Durant’s ledger and asks Cullen to help her take down the Durants so they can run the railroad themselves. Cullen refuses and urges Lily to be careful. When Elam tells Lily that Durant hired him to kill her, she convinces Elam to join her and Cullen against Durant.
Eva visits Elam’s riverside house to end their affair, but Toole finds them there together and commits suicide in front of Eva.
Joseph shows Cullen a sprawling Sioux camp nearby, alerting him to an impending attack. In town, The Swede returns, badly burned. He explains that the Sioux discovered he was not The White Spirit and asks forgiveness for betraying Hell on Wheels.
The town defends Hell on Wheels as the Indians attack. Cullen protects the bridge, while Elam rescues Eva from his burning riverfront home. The Swede dances in the street as the town goes up in flames.
When the attack is over, The Swede strangles Lily in an effort to hurt Cullen. Cullen takes The Swede out to the bridge and ties a noose around his neck, but The Swede leaps into the river before Cullen can secure the rope.
An interrogator later informs Cullen that Durant is in custody, and asks Cullen to step in and finish building the railroad.