The fight which was labelled as the 'Fight of the Century' took six years to organize after claims that Mayweather was still avoiding Pacquaio.
But finally Mayweather, 38, delivered a defensive masterclass against his rival, Pacquiao, 36, at the MGM Grand Garden Arena in Las Vegas.
Mayweather, who added the WBO welterweight title to the WBC and WBA titles he already owned, was awarded the fight 118-110, 116-112 and 116-112 by the three judges.
With his victory, Mayweather also cemented his status as the greatest pound-for-pound boxer of his generation.
The five-weight world champion is now undefeated in 48 professional fights, stretching back 19 years.
Six-weight world champion Pacquiao, who falls to 57 wins, six losses and two draws, thought he had won the bout.
Rival broadcasters Showtime and HBO joined forces for the first time since Lennox Lewis fought Mike Tyson in 2002 to show the fight, with Jimmy Lennon Jr and Michael Buffer sharing ring announcer duties.
A-listers in the 16,507 crowd included actors Clint Eastwood and Robert De Niro, singers Sting and Prince, US tycoon Donald Trump and many others.
Multi Grammy Award winner Jamie Foxx sang the American national anthem prior to the fighters entering the ring. So prized was a seat that many celebrities were even sat behind the press row.
Pacquiao began his ring walk at 20:45 Vegas time - to the strains of a song he recorded especially for the occasion - and was awarded a rapturous reception. Mayweather, on the other hand, was roundly booed, despite being effectively the house fighter.
The opening round was extremely cagey, with both men trying to establish their distance, but Mayweather did land with a couple of eye-catching right hands on the counter.
Not only did Mayweather look noticeably bigger than Pacquiao, he also looked quicker in the early rounds.
And when Pacquiao did get close, Mayweather was content to tie him up, to both Pacquiao and the fans' frustration.
Mayweather rocked Pacquiao with two more rights in the second, although Pacquiao was able to get inside his rival's superior reach and unleash a couple of flurries.
The third round was a more even affair, with Pacquiao able to draw Mayweather into some exchanges and Mayweather doing plenty of rough stuff on the inside.
Pacquiao really came into the fight in the fourth, staggering Mayweather with a left hand, which many thought would be a key weapon in this fight.
By the eighth round, the fight had become a chess match. Mayweather moved and picked his opponent off with the jab. Pacquiao was only landing with 18% of his punches, far fewer than his usual average of 34%.
When the 10th arrived the cocky Mayweather was back, smiling and dropping his hands to taunt an increasingly frustrated Pacquiao.
The Pacquiao corner knew a knockout was required but their man had to catch his fleet-footed opponent in the opposite corner first.
Alas, it was a task the crowd favorite could not rise to, although the fighter himself felt he had done enough to claim victory.
"He is moving around and it's not easy to throw a lot of punches if your opponent moves around. I can handle his power, it's not strong like other opponents. It's not about size. I've been fighting bigger than him and it's not a problem."
"I was a smart fighter, I out-boxed him," said Mayweather, shaking off boos from the crowd which was unimpressed with his defensive style.
"We did what we had to do tonight. I knew he was going to push me. He had moments in the fight but I kept him on the outside."
"He's a hell of a fighter. Now I see why he is one of the guys at the pinnacle of the sport of boxing."
Afterwards Mayweather confirmed he would fight one more time in September before retiring.
Mayweather will get 60 percent of the bout's total revenue, and Pacquiao 40 percent — which, according to some estimates, may be $180 million and $120 million respectively.
- Agencies