The undefeated six-time world champion announced on his Twitter feed Tuesday he will end a 16-month hiatus when he faces WBC welterweight champion Victor Ortiz on September 17.
Mayweather (41-0, 25 KOs) hasn't fought since a unanimous decision over Shane Mosley on May 1, 2010, and has repeatedly declined to accept a bout against WBO welterweight champ Manny Pacquiao — a dream ticket many boxing fans are eager to witness.
Instead, it was Mosley who squared off with Pacquiao in May, losing to the Filipino star in a lopsided 12-round decision.
Ortiz (29-2-2, 22 KOs) is riding a six-match win streak, most recently defeating Andre Berto in April to claim the WBC crown in a fight many consider the year's best.
"I am ready to return to the ring and give my fans a fantastic night of boxing by fighting the best out there for me; that is Victor Ortiz," Mayweather said in a statement. "At this stage of my career, these are the challenges I look for, a young, strong, rising star looking to make his mark in boxing by beating me.
"Trust me, I will be ready."
The 24-year-old Mexican-American is one of the sport's strongest young fighters.
"I respect Mayweather because he has been a champion for many years and I know he will be ready, but so will I," Ortiz said. "I'm a world champion for a reason and I am not going to let go of my title any time soon. This is going to be a great fight, but I will remain a world champion for many years to come."
The 34-year-old Mayweather's time away from the ring has been riddled with legal troubles.
He faces felony charges from a domestic argument with his ex-girlfriend and two of their children last year, and he faces misdemeanor harassment charges accusing him of threatening two homeowner association security guards outside his Las Vegas home. The charges stem from an October dispute over parking with guards in the gated community where the prizefighter lives.
Mayweather also faces a September trial on a misdemeanor battery charge stemming from allegations that he poked a 21-year-old guard in the face during a separate argument over parking tickets in November.
The venue for the September fight has yet to be determined.