Wade Wilson, a former special forces operative turned mercenary with a quick wit and a twisted sense of humor, lives in New York City where he meets and falls in love with Vanessa, a local escort. Their relationship progresses rapidly, both bonding over their eccentricities and traumatic pasts. However, their happiness is shattered when Wade is suddenly diagnosed with terminal cancer, leaving him with a grim prognosis. Desperate to find a cure and unwilling to leave Vanessa bereft, Wade leaves her without explanation to undergo a risky treatment he hopes will save his life.

The treatment, offered by a shadowy organization under the guise of a cancer cure, subjects Wade to extreme torture in an attempt to activate latent mutant genes. The experiment is run by Ajax, a sadistic scientist with enhanced strength and a pain insensitivity who aims to create super-powered slaves to sell to the highest bidder. The procedure eventually grants Wade extraordinary regenerative abilities that cure his cancer but severely disfigure his appearance. Mentally and physically scarred, he adopts a new identity with a costume to mask his disfigurement, and armed with his new powers and a twisted sense of humor, he sets out on a quest for revenge against those who have wronged him, all while trying to stay out of the sight of his beloved Vanessa.