A fluid counter-punching strategy led the 35-year-old to a comfortable win over the Puerto Rican, whose late rally sparked the partisan crowd into life but failed to make much impact outside of busting Mayweather's nose.
Mayweather appeared to coast late on, before looking frustrated with his inability to finish his opponent off in the final round with a hard uppercut and several further crunching blows, but was good value for his win over the 12.
'Money' will now head into his upcoming jail sentence with a record of 43-0, inflicting upon Cotto his third defeat with scorecards of 117-111, 117-111 and 118-110.
The American tipped his hat to tough Puerto Rican Cotto after the fight.
"You're a hell of a champion. You're the toughest guy I ever fought," he said. "You want to give the fans what they pay for and that's excitement. It comes with the territory when you fight a future Hall of Famer like Miguel Cotto.
"I had to fight hard and suck it up. I dug down and fought him back."
Mayweather added that he is still keen to face Manny Pacquiao.
"I tried to make the Pacquiao fight and that didn't work, so I fought Miguel Cotto instead and gave the fans a great fight," Mayweather said. "I want to fight Pacquiao but he has to take the test, and I'll fight him."
Cotto was philosophical after his defeat, saying that he could not have done any more to try and dethrone Mayweather.
"The judges said I lost the fight. I can't do anything else," he said. "I have to take my defeat.
"He knows what kind of fight Miguel Cotto brings, and so do the fans. I'm happy with my fight and with my performance and so is my family. I can't ask for anything else."
Round one: Mayweather connects with the first few jabs of the contest in the opening minute, and continues to catch Cotto with some ultra-fast shots whenever the champion gets close. Cotto looks happy to absorb these initial shots but isn’t able to connect too well with his own attacks. Cotto 9-10 Mayweather
Round two: Cotto starts the second cornering the challenger before pretty much hoisting Mayweather off his feet with a grab in the opening minute. The jab remains all Mayweather but Cotto brings the crowd to life with a flurry to the body halfway through the round. Mayweather connects with a few more shots whilst evading the champion’s wild swings in the closing 30 seconds and that’s another one for ‘Money’. Cotto 18-20 Mayweather
Round three: Mayweather develops a confident smirk as Cotto continues to miss the majority of his hooks, and the challenger is beginning to occupy the centre of the ring a lot more now as he dictates the flow. The least eventful of the opening three rounds but nonetheless the tide remains against the champ. Cotto 27-30 Mayweather
Round four: Cotto has landed 26 of 138 punches from the first quarter of the fight, which speaks volumes so far. Mayweather lands a powerful pair of jabs to the face of the champ in the opening minute, and begins to look for the opening with strong combinations but Cotto replies with his best offense of the fight so far in the closing 40 seconds. Cotto 36-40 Mayweather
Round five: The champion looked bruised and frustrated in his corner, and comes out aggressively in the fifth. Mayweather soaks up the onslaught and gains enough distance to begin counter-punching though he is evading less now than in the first four. The challenger is spending more time back in the corner with Cotto and it pays off towards the end of the round with further shots on the break. Cotto 45-50 Mayweather
Round six: There is now a small opening above the left eye of Cotto, and a grinning Mayweather continues to lure the champion in for counter-strikes but this is the challenger’s quietest round yet. A choice left with 2:10 remaining lands on ‘Money’ without reply. Cotto 55-59 Mayweather
Round seven: Mayweather is back in the middle for the early stages of the seventh and connects well one minute in. Cotto swings several flurries but is being caught on the outside by the challenger. Cotto 64-69 Mayweather
Round eight: Mayweather lands an early uppercut but to Cotto’s credit, he is soaking up the shots from his challenger. His own rallies still fail to register on ‘Money’, who finally lands a few more head shots in the final 70 seconds and busts Mayweather’s nose. The pro-Cotto crowd are given reason to get behind their man with that round. Cotto 74-78 Mayweather
Round nine: A quiet round between the ropes but the previous three minutes has certainly awoken the crowd. Cotto may well be on a second wind here, and has the slightest of edges in a relatively tame ninth. Cotto 84-87 Mayweather
Round 10: Cotto has a little momentum and looks to turn up the pressure, but the counter-punching of Mayweather is returning to the heights from earlier in the fight and with six minutes remaining that is an important round for the challenger after losing his way for a while. Cotto 93-97 Mayweather
Round 11: The champion tries to keep Mayweather penned in the corner but even his best flurries are struggling to phase the 35-year-old. The challenger moves into the middle to deliver a few select shots which rubber-stamp another round, and Cotto will need to somehow knock out the man he has barely troubled to keep his title. Cotto 102-107 Mayweather
Round 12: Mayweather finishes strong with an uppercut halfway through the closing round which loosened Cotto’s legs momentarily but he is unable to finish the fight with further solid shots in the final 60 seconds and at the final bell Cotto cuts the figure of a man who knows his reign is up.
The final Eurosport scorecard is 117-111 to Mayweather.
Two of the three Nevada judges agree, with a further score at 118-110 all in the favour of Mayweather, the new champion.