The hip-hop star accompanied the fighter as he made his way to the ring from his dressing room and then performed new track No Worries before the welterweight championship bout.
The fight night appearance in Las Vegas came at the end of a tough week for Lil Wayne, who suffered another seizure and lost his endorsement deal with Pepsi due to backlash over his controversial lyrics on Future's Karate Chop track.
The bosses of Mountain Dew dropped him as their brand representative after he upset the family of slain Emmett Till by using the tragic teenager's name in an ill-advised rap.
His pre-fight performance gave pal Mayweather, Jr. the edge he needed - the boxer beat contender Robert Guerrero in a unanimous decision.
The undefeated champ has declared he'll fight five more times before retiring.