The film opens with Wade Wilson (Deadpool) living a quiet, civilian life, having retired his mercenary persona after failing to join the Avengers in a previous timeline. His domestic bliss is abruptly interrupted when the Time Variance Authority (TVA), led by Agent Paradox, captures him.

The Mission to Save the Timeline Paradox reveals that Wade's universe (Earth-10005, the Fox X-Men timeline) is facing imminent and irreversible deterioration because its "anchor being," Logan (Wolverine), has died (referencing the events of Logan (2017)). The TVA plans to use a "Time Ripper" device to accelerate the destruction of this timeline to prevent it from collapsing into the main Sacred Timeline (Earth-616).

Wade, determined to save his friends and his reality, rejects the TVA's offer of safety and convinces Paradox to give him a chance to find a living variant of Logan to act as the new anchor.

Deadpool travels through the multiverse and eventually finds a variant of Logan (Wolverine), who is weary, guilt-ridden, and harbors deep resentment over his past failures (including letting his fellow X-Men die). This variant is often referred to as the "worst Wolverine."

Wade convinces the reluctant Logan that the TVA has the power to fix his past universe, and the two are ultimately sent by Paradox to The Void, a desolate wasteland at the end of time where the TVA dumps pruned timelines and rejected variants.

In the Void, Wade and Logan encounter Cassandra Nova, the powerful and malevolent twin sister of Professor Charles Xavier. Cassandra is the film's main antagonist, commanding a ragtag army of rejected variants including various versions of Deadpool and classic Fox X-Men villains.

Logan and Wade initially fight but are forced to work together, forming an unlikely and begrudging buddy-comedy dynamic. They rally a resistance group of exiled heroes (including familiar faces like Elektra and X-23) to confront Cassandra, who plans to use the Time Ripper to destroy all timelines, leaving only the Void.

The final confrontation takes place back in Earth-10005. Wade and Logan, with the unexpected help of allies like Peter (an ordinary citizen with a good heart), battle Cassandra's forces.

Paradox reveals that the only way to stop the Time Ripper is for one or both of them to disrupt its power flow, a sacrificial act that would likely kill them. Wade and Logan ultimately destroy the Time Ripper together by sharing the massive energetic burden, which results in Cassandra's defeat and death.

In the aftermath, Paradox is arrested by Hunter B-15 for acting without authority. Hunter B-15 confirms that their heroic actions have stabilized Earth-10005, preventing its deterioration. Wade asks for two things: to save the resistance group from the Void and to change the history of Logan's world. B-15 grants the first request but denies the second, explaining that Logan's difficult past is what shaped him into the hero he needed to be.

The film concludes with Logan deciding to stay in Wade's universe, finally finding redemption and a place to belong alongside Wade and his friends.