Mosley has never been knocked out. He spent much of the final three-quarters of the bout on the defensive, drawing intermittent boos from a reported crowd of more than 16,000.
Pacquiao continually pressed the action, moving forward from a southpaw stance with flicking right jabs and occasionally stinging straight lefts that caused moderate swelling on Mosley’s face.
He outpunched Mosley, 552-260, and outlanded him by a 182-82 count.
The win, which improved the Filipino to 53-3-2 in a pro career that began in 1995, came by scores of 119-108, 120-108 and 120-107.
Sports Network scored it 118-109.
"I don't care who my next opponent is. I'd be satisfied with what I've done in boxing," Pacquiao said, answering a query about his desire to fight enigmatic pound-for-pound elitist Floyd Mayweather Jr.
"I want the fight because the people want it."
Pacquiao has won 14 straight fights since a unanimous decision loss to Erik Morales at 130 pounds in March 2005, also at the MGM Grand.
"I was in there with the best tonight," said Mosley, now winless in three fights (0-2-1) since defeating Antonio Margarito in January 2009.
"He surprised me with his punching power. That was the most legitimate knockdown I've had against me in a long time, and I said to myself, 'Wow, this guy's really got some power.'"
The defeat of Mosley was Pacquiao's second successful defense of the WBO welterweight title he won via 12th-round stoppage from Miguel Cotto in November 2009.
Mosley, a former champion at 135, 147 and 154 pounds, fell to 46-7-1. He sidestepped immediate post-fight questions about retirement, refusing to blame the loss on advanced age.
"I thought I did a pretty good job," he said. "I can still get in there with young guys and do what I do. This guy is amazing."
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On the undercard: Mexican veteran Jorge Arce won his third weight-class championship with a dramatic 12th-round stoppage of incumbent Wilfredo Vazquez Jr. in a WBO junior featherweight title bout.
Vazquez, who scored the lone knockdown with a counter left hand in the fourth, tired badly in the late going and was pinned against the ropes for a lengthy flurry before his corner - led by his father, three-time champion Wilfredo Vazquez Sr. - threw in the towel at the 55-second mark of the final round.
Arce, a former champion at 112 and 115 pounds, was leading 107-102 on one scorecard at the time of the stoppage while the final two cards were even at 104-104.
He is 57-6-2 and scored his 44th knockout while improving to 12-4 in championship fights.
Vazquez, who'd won his belt 15 months ago and defended twice, fell to 20-1-1.
Sports Network had Vazquez ahead, 105-103, at the time of the stoppage.
* * *
Comebacking ex-champion Kelly Pavlik returned after 13 months on the shelf with a combative 10-round decision over previously unbeaten Texan Alfonso Lopez in a super middleweight bout.
Pavlik, who recently completed a stint in rehab for alcohol dependence, won two scorecards with counts of 98-92 and 99-91 to override a 95-95 result on the final card.
A title-holder at 160 pounds from 2007-2010 before losing his belts to Sergio Martinez, he is 37-2.
Lopez is 21-1.
Sports Network scored it 96-94 for Pavlik.
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Junior welterweight Mike Alvarado won the vacant WBC Continental Americas championship and moved to 30-0 overall when opponent Ray Narh quit on his stool at the end of three rounds of the scheduled 10-rounder. Narh is 25-2.
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Former 108-pound world champion Rodel Mayol scored a majority decision over Javier Gallo in 10-round junior bantamweight bout, winning two scores of 98-92 to overrule a third card that read 95-95. Mayol improved to 28-5-2 while Gallo is now 17-4-1.
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French-Canadian junior welterweight Pier Olivier Cote is 16-0 with 11 KOs as a pro after his fourth-round TKO of Aris Ambriz in a scheduled eight-rounder. Ambriz dropped to 15-2-1.
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Unbeaten lightweight prospect Karl Dargan won his ninth straight with a unanimous six-round decision over Randy Arrellin, earning the verdict by scores of 60-54, 60-54 and 59-55. Arrellin is 8-5.
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Eighteen-year-old knockout artist Jose Benavidez improved to 11-0 and scored his 10th stoppage with a fifth-round TKO of James Hope in a junior welterweight bout scheduled for six. Hope fell to 6-8-1.