In a Louisiana assisted-living home in 1999, Paul Edgecomb begins to cry while watching the film Top Hat. His companion Elaine becomes concerned, and Paul explains to her that the film reminded him of the events of 1935, which took place when he was a prison officer, in charge of death row, what they refer to as the "Green Mile".

In 1935, Paul supervises officers Brutus Howell, Dean Stanton, Harry Terwilliger, and Percy Wetmore at Cold Mountain Penitentiary. Paul is suffering from a severe bladder infection and receives John Coffey, a physically imposing but mentally challenged black man, into his custody. John had been sentenced to death after being convicted of raping and murdering two white girls. One of the other inmates is a Native-American named Arlen Bitterbuck, who is charged with murder and is the first to be executed. Percy demonstrates a severe sadistic streak, but, as the nephew of Louisiana's First Lady, he cannot be held to account; he is particularly abusive towards inmate Eduard Delacroix, breaking his fingers, killing his pet mouse Mr. Jingles, and calling him "faggot". In exchange for resigning from the penitentiary and accepting a job at an insane asylum, Percy is allowed by Paul to oversee Del's execution; at the execution, Percy deliberately avoids soaking the sponge used to conduct electricity to Del's head, leading to Del suffering a gruesome death with Paul and the others in attendance.

John begins to demonstrate supernatural powers; he cures Paul's bladder infection, resurrects Mr. Jingles, and heals Melinda Moores, wife of the prison's chief warden, of a brain tumor. This last affliction he releases into Percy, who under its influence shoots prisoner William Wharton to death. Wharton had from the moment of his arrival been a troublemaker; he assaulted the guards as he was being escorted into the block, made mischief on two occasions that later caused Paul to order him restrained in the block's padded cell, groped Percy, racially insulted John, and revealed psychically to John that he is, in fact, responsible for the crime for which John was condemned. John then reveals the story psychically to Paul, and, when doing so, he also releases his supernatural energy into Paul. Meanwhile, Percy is committed to the insane asylum.