In the year 2029, mutants are on the brink of extinction, with no new mutants having been born in 25 years. Meanwhile, an aging and weary Logan, formerly known as Wolverine, works as a chauffeur in Texas. His healing factor has faltered, and his adamantium-coated skeleton is gradually poisoning him, so his body has aged greatly and is in constant pain. Along with mutant tracker Caliban, Logan cares for Professor Charles Xavier, who occasionally suffers seizures, loses control of his telepathic abilities and unintentionally paralyzes people around him. Logan plans to raise enough money, buy a boat and live the rest of his days with his fellow mutants in isolation.

Gabriela Lopez, a nurse for biotech corporation Alkali/Transigen, hires Logan to escort her and an eleven-year-old girl named Laura to a safe haven in North Dakota. Desperate for money, Logan accepts the offer. Transigen's mercenaries, consisting of Donald Pierce and his Reavers, find Gabriela and kill her. Logan, Xavier, and Laura narrowly escape, but Caliban is captured and forced to use his mutant tracking powers to find the trio.

Logan learns that Laura is one of many mutant children Transigen was breeding as part of the "X-23" project. Upon completing the "X-24" project, Dr. Zander Rice, the head researcher, deemed the children obsolete and ordered them euthanized. Gabriela helped free many children and personally escorted Laura, who carries Logan's DNA. The Reavers catch up with them in Oklahoma City, but Xavier suffers a seizure and telepathically freezes everyone in the hotel, allowing the trio to escape.

On the road, they help farmer Will Munson and his family after a traffic incident. Grateful, the Munsons invite them over for dinner, and they accept. When a nearby pipe springs a leak, Logan and Will leave the house to fix it. While Logan is gone, Xavier recalls a telepathic seizure he had in Westchester, which claimed the lives of many people, including several X-Men. He expresses his guilt to a person he thinks is Logan but is actually X-24, a feral clone of Logan with severely limited healing factor. X-24 fatally stabs Xavier, kills Will's family and abducts Laura. Logan and Will engage the clone and incapacitate him, but Will dies from his injuries. Caliban, who is locked up in a van outside the house, sacrifices himself by setting off a pair of grenades which destroys the van, but fails to kill Rice and Pierce. Logan retrieves Laura and escapes with Xavier's body.

After burying Xavier, Logan and Laura make their way to the safe haven and meet Rictor and the other Transigen test subjects that managed to escape. Believing his job is done, Logan prepares to leave, but changes his mind when he sees the Reavers pursuing the children. Using a serum that briefly boosts his healing factor, Logan engages and kills the majority of the mercenaries. When the serum wears off, Rice confronts Logan and reveals that the destruction of mutantkind was due to a genetic dampener created by his company and distributed via commercial food and drink products. Horrified and outraged, Logan shoots Rice dead. Pierce releases X-24, who engages Logan. The children kill the remaining Reavers, including Pierce.

Logan and Laura fight X-24 and overpower him, and Rictor, using his seismic powers, helped them to temporarily defeat the clone by dropping a truck on him. After recovering, and realizing that a severely weakened Logan is no match for him, X-24 impales Logan on the sharpened branch of a felled tree. Before he can deliver the killing blow, Laura shoots him in the head with an adamantium bullet stolen from Logan, killing him. Grievously wounded and near death, Logan tells Laura not to be the weapon she was made to be, and acknowledges her as his daughter before he finally succumbs to his wounds and dies in her arms. Later, the children bury Logan's body, then head for the border. Before Laura joins the others, she tearfully says goodbye to Logan, and rotates the makeshift cross adorned on his grave to form an 'X', honoring him as the last of the X-Men.

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