In the Harlem neighborhood of New York City, Carl Lucas and Willis Stryker, enforcers for local mobster Sonny "The Hammer" Caputo, participate in a store robbery where several innocents end up killed. Afterwards, however, Lucas confesses to Stryker, who is a longtime friend of his, that he doesn't want a life of crime anymore. Stryker tries to talk Lucas out of his decision, but in the end, honors his decision. Abandoning Caputo's gang, Lucas seeks refuge with his father, James, who intends to help Lucas seek legitimate employment. Meanwhile, Caputo, angered at Lucas' desertion, orders a hit on Stryker in order to find out Lucas' whereabouts, which leads to Stryker's girlfriend, Reva Connors, to break up with him out of fear for his well-being. Angry at Lucas, believing him to be responsible for the breakup, he plants a cache of illegal drugs in the the Lucas' house and leaves an anonymous tip to the police. While he and his father are at home, the police suddenly show up and arrest Lucas on the spot. Because of Caputo's influence, Lucas is immediately sent to prison without a trial.
Enraged at the unfairness of his situation, Lucas attempts to escape from the prison on his first night, but is unsuccessful and ends up in a violent brawl with several prison guards, where he ends up actually killing one. This leads to Lucas being transferred to Seagate Prison off the coast of Georgia. Upon his arrival, he encounters Albert Rackham, a racist and sadistic guard who subjects Lucas to brutal beatdowns and verbal assaults almost 24/7 during his first few weeks at the prison. After a month, Lucas snaps and fights Rackham back. Eventually, the brawl is broken up by the Warden and other guards (who are much fairer than the ones in New York City) They put Lucas on probation but come to his defense in that he was provoked first and was defending himself. Meanwhile, Rackham is demoted and has his pay suspended for several months.
The next day, Lucas is visited by research scientist Dr. Noah Burstein, who works part-time at the prison. He comments that he observed Lucas' fight with Rackham and "saw something" in him, asks Lucas to volunteer for an experimental program where he would be subjugated to a formula similar to Dr. Abraham Erskine's Super-Soldier serum, which Lucas agrees to. Taking him to a medical lab in the prison, Dr. Burstein immerses Lucas in an electrical field conducted by an organic chemical compound. In the middle of the process, Dr. Burstein leaves the lab in order to retrieve his notes, leaving Lucas unattended. While he is alone, Rackham sneaks into the lab and tampers with the controls, hoping to kill Lucas. Dr. Burstein walks in on this and alerts the Warden. However, once the process is complete, Lucas is not killed; instead, he has received body-wide enhancements that has given him superhuman strength and durability.
- Curtis "50 Cent" Jackson as Luke Cage
- Bill Nighy as Dr. Noah Burstein
- Lester Speight as Diamondback / Willis Stryker
- Giovanni Ribisi as Sonny "The Hammer" Caputo
- Hulk Hogan as Albert Rackham
- Gabrielle Union as Dr. Claire Temple
- Keshia Knight Pulliam as Reva Connors
- John Malkovich as Gideon Mace
- Sidney Poitier as James "Big Jim" Lucas