All three ringside judges scored the bout at 117-111 to the world's top pound-for-pound boxer, competing in his first fight since he outpointed Miguel Cotto exactly a year ago before serving time in jail last summer.
Though 'The Ghost' brought the uncompromising high-pressure attack he has become known for, Mayweather's own trademark defence was just too quick and too elusive for the most part, with the champion's stinging counter-right catching Guerrero time and time again throughout the contest.
Mayweather opened up two small cuts on his opponent just after the halfway mark, one on his left eye and another on his nose, but took his foot off the pedal in the latter stages knowing he had the fight won.
There were occasional boos from the crowd at the MGM Grand Garden Arena due to the numerous periods of relative inaction, but for the 44th consecutive outing the 'Mayweather code' remains uncrackable.
After the bout, Mayweather defended the presence of his father, Floyd Senior, throughout the fight camp despite his constant bickering with Guerrero's father Ruben.
"I needed my father for this fight because Guerrero is tough, a true warrior," Mayweather said.
"My father helped my defence and encouraged me to box smart. I wanted a knockout but I hurt my right hand during the bout."
"I am 36 and after the Cotto fight I wasn't sure if my defence was sharp enough but it was, even with the sore hand. Guerrero was pressing with his attack but him pushing me to perform was what I needed."
The disappointed but classy Guerrero commended the victor, saying: "Floyd was barely slipping by my punches but his defence is real good, everything happens for a reason and I will keep fighting and put myself back in a good position. Maybe I can get a shot at Floyd again before he retires."
In the chief support bout, Abner Mares became a three-weight world titlist in his step up to featherweight, stopping good friend Daniel Ponce de Leon in the ninth round for his WBC strap.
Mares began strong and looked like he had been a featherweight for years, knocking down the incumbent in round two before Ponce de Leon battled back in the middle rounds.
But a second knockdown came in round nine from a crunching right hand, and Mares’ follow-up assault rightly compelled the official to stop the bout.
Similarly, Leo Santa Cruz finished off Venezuela’s Alexander Munoz with a crushing TKO after five one-sided rounds in his move up to junior featherweight.
It was undefeated Santa Cruz’s 14th knockout success as his record moves to 24-0-1, while Munoz’s record now reads 36-5.
J’Leon Love stayed undefeated at 16-0 thanks to a highly dubious split decision over middleweight Gabriel Rosado (21-7) in the ‘May Day’ pay-per-view opener.
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