The hometown fighter has weathered a slew of demanding challenges since turning pro after the 1996 Olympics, from brawlers, veterans and distinguished champions.
The one common link — Mayweather always left the ring with a win.
Here's The Times' ranking of Mayweather's five greatest fights:
For years, Mayweather believed, the most significant impediment to his ability to collect the riches his boxing talents deserved was the attention heaped on De La Hoya.
Their May 2007 fight at MGM Grand still stands as the best-selling pay-per-view fight in history with a record 2.48 million buys.
De La Hoya's strategy to rely on his jab was working, but midway through the bout as the older fighter began to fatigue, the jab went absent. "I could see his shots coming, and I stayed outside," Mayweather said after taking the fifth and sixth rounds on all three scorecards.
Two more good rights in the eighth by Mayweather changed the fight's course.
Punch statistics for the fight showed Mayweather landed 207 to De La Hoya's 122, and 138 power punches to De La Hoya's 82.
But the scorecards were close: Judge Tom Kaczmarek gave De La Hoya a 115-113 edge, Chuck Giampa ruled Mayweather won 116-112, and Jerry Roth's deciding margin was 115-113 to Mayweather.
"Look at the punch-stat numbers, and you can see why I'm the new champion tonight," Mayweather said. "I just fought the best fighter in our era, and I beat him."
2. Miguel Cotto
Cotto didn't beat Mayweather in May 2012, but he brought the champion down a peg or two.
The stoic Puerto Rican had won three consecutive fights after a 12th-round technical knockout loss to Pacquiao in 2009.
Cotto, a well-schooled body puncher, challenged Mayweather, who answered with repetitive and accurate punches and won at least four of the first six rounds on the scorecards. Cotto swept the sixth.
Mayweather was aware he was in a fight to win over the judges, and pressed the action in the ninth, sweeping that round, the 10th and the 11th, by relying on brilliant combinations and effective counterpunches. Cotto couldn't match Mayweather's legendary conditioning.
Judges Robert Hoyle (118-110), Patricia Morse Jarman (117-111) and Dave Moretti (117-111) awarded a margin wider than the action appeared.
Mayweather was so visibly beaten up after the bout he replaced his uncle/trainer, Roger Mayweather, with his defense-minded father, Floyd Mayweather Sr., as head trainer.
In the ring after the fight, Mayweather Jr. embraced Cotto and told him, "You are a hell of a champion — the toughest guy I fought."
3. Saul "Canelo" Alvarez
The hope that Mayweather could lose keeps drawing a heavy number of pay-per-view buys.
Proof came in September 2013, when fan favorite and Mexico's then-unbeaten Alvarez was matched against Mayweather in a fight that would set a record $150 million in total pay-per-view sales.
Alvarez trained in Big Bear, so his conditioning would allow him to swarm Mayweather and land heavy punches on the elusive fighter.
The masses ate it up, but he became another in Mayweather's list of beaten foes of Mexican descent. From the start, Mayweather delivered a professorial performance over the younger Alvarez. While Judge C.J. Ross scored the bout even, on her way out of the sport, everyone else had it as a Mayweather landslide.
Mayweather's speed ruled the early portion of the fight.
Times columnist Bill Dwyre wrote, "By the seventh, Mayweather was in complete control. He was on Floyd cruise, darting in at will, connecting on four or five jabs at a time. At one point, he had Alvarez in the corner for 30 seconds and just slapped away, mostly at will."
4. Jose Luis Castillo rematch
Mayweather complained of a sore shoulder after escaping with a unanimous decision over Castillo in April 2002, in what is widely viewed as the closest thing to a loss on his record.
Punch stats in their first meeting showed Castillo landed 203 punches, while Mayweather connected on only 157 punches.
Mayweather returned eight months later with a far more convincing triumph in the Dec. 7, 2002, rematch.
The rematch was fought at Mandalay Bay in Las Vegas, with Mayweather producing what The Times reported as a "masterful" performance in what most observers considered a calculated boxing show that left nothing to doubt.
The Times' Steve Springer wrote, "As the fight wore on, Castillo, his nose bloodied from the fourth round on, labored to merely lay a glove on Mayweather. A punch seemed out of the question."
5. Genaro Hernandez
Mayweather's technical brilliance has gotten him past several fighters who were considered too tough for him.
Such was the case when Mayweather won his first world title, on Oct. 3, 1998, against East Los Angeles' Hernandez, then-defending World Boxing Council super-featherweight champion who had won a string of tough brawls at the Forum in Inglewood. Hernandez's only loss before Mayweather was to Oscar De La Hoya in a bout for L.A. bragging rights.
Mayweather was a 21-year-old who had become the first U.S. 1996 Olympic boxer to land a title shot.
For the bout, televised by HBO from Las Vegas, Hernandez, 32, was paid $600,000, while Mayweather earned a purse of $150,000.
Hernandez was simply picked apart by Mayweather. Judge Bob Logist awarded Mayweather each of the first eight rounds and the other two judges had it scored, 79-73, in the youngster's favor. "It took me a couple rounds to feel him out," said Mayweather. "But after the second round, I started using my jab, and then I took control of the fight."
The difference in skill was so wide that Hernandez didn't answer the bell for the ninth round. In 2011, Hernandez died of cancer, and his funeral at Resurrection Church in East L.A. was paid for by Mayweather.
Read the Los Angeles Times' special edition Flipboard digital magazine Mayweather vs. Pacquiao.