Nearly twenty years after stealing money from his friends and making a new life in Amsterdam, 46-year-old Mark Renton suffers a heart attack in a gym. Though two decades sober from heroin, he is now undergoing divorce and facing imminent redundancy. Facing a mid-life crisis, he decides to take a nostalgic trip back to Edinburgh. Daniel "Spud" Murphy has returned to a cycle of heroin addiction after separating from his wife, Gail, and losing custody of his teenage son, Fergus, born after Renton had left. Simon "Sick Boy" Williamson abuses cocaine, engages in blackmail schemes with his Bulgarian girlfriend, Veronika, and runs a failing pub which he inherited. Meanwhile, Francis "Franco" Begbie is serving a prison sentence.
Renton visits Spud in his flat on the top floor of a high-rise just in time to save him from a suicide attempt. Spud is initially angry, but Renton offers to help him overcome his addiction. Renton next visits Sick Boy, who, after a seemingly friendly conversation in which Renton gives the impression his life in Amsterdam is going well, attacks him, still furious from being ripped off. Veronika's intervention saves Renton, who then produces a package, giving Sick Boy back his original share of the money. Unimpressed, Sick Boy plans to take revenge.
Begbie escapes from prison and returns to his estranged wife June's flat, meeting his college-bound son, Frank Jr., whom he forces to join him in burgling houses. He visits Sick Boy, who pretends to have heard of Renton living in Amsterdam and promises to provide Begbie with a false passport so he can travel to the Netherlands to exact revenge.
Renton, Sick Boy, and Veronika fraudulently apply for a £100,000 EU business development grant to turn the pub's upper floor into another business venture: a brothel disguised as a sauna. Veronika finds herself attracted to Renton, and they begin an affair. Meanwhile, Spud joins the renovation and befriends Veronika, who inspires him to write his memoirs. One of Sick Boy's blackmail targets reports him to the police, and Renton seeks legal advice from his ex-girlfriend, Diane Coulston, now a solicitor. The proceeds of their crimes are used up in legal fees and Sick Boy's cocaine addiction. Renton escapes from Begbie after a chance encounter at a nightclub, but Doyle, owner of a rival brothel, kidnaps him and Sick Boy, drives them to the countryside, and intimidates them into abandoning their scheme, leaving them to walk back to Edinburgh naked.
Begbie visits Spud and, reading his memoirs, discovers that Renton left Spud his share of the money. Veronika arrives, and Begbie steals her phone, with which he sends messages to Renton and Sick Boy pretending to be her and asking them to come to the pub at midnight. Veronika takes Spud to her apartment and asks him to leave with her, promising him half of the £100,000. Spud fears he will spend it on heroin again, so she offers to give his share to Gail and Fergus. He helps transfer the money to Veronika's account by forging Renton's and Sick Boy's signatures. After reading another excerpt of Spud's writings about their encounter with Begbie's alcoholic father in the derelict Leith Central railway station, Begbie visits June's flat for the last time, apologising to Frank Jr. for his abuse and giving him words of encouragement.
Spud arrives too late at the pub to warn his friends of Begbie's ploy. Begbie knocks Sick Boy unconscious and chases Renton across the upstairs floor. He throws Renton through the floorboards, leaving him hanging by the neck from electrical wiring; Begbie tries to strangle him, but Sick Boy douses him with pepper spray and saves Renton. Begbie pulls out a sawn-off shotgun and tries to kill them both, but Spud hits him with a toilet bowl.
They leave Begbie in the boot of Sick Boy's car outside the prison. Veronika returns to her son in Bulgaria. Spud puts together his book of memoirs and mends his relationship with Fergus and Gail, who suggests the title "Trainspotting." Renton and Sick Boy resume their old friendship. Renton moves back into his now-widowed father's home and embraces him in reconciliation before going to his bedroom and dancing to a remix of "Lust for Life".
