Two of the three scorecards had Mayweather winning 116-112 and 115-113, with De La Hoya winning one card by 115-113.
The final round ended with the fighters exchanging a flurry of punches, but most observers felt Mayweather used his superior speed to garner enough points for a win, before the decision was announced to a sellout crowd at the MGM Grand Hotel.
The bout is expected to generate a $100 million revenue take. The pay-per-view revenues succeeded what fight promoters expected before the fight.
As promoter of the fight, De La Hoya was guaranteed $25 million. Mayweather got $10 million.
Mayweather rose to 38-0 with 24 KOs, and De La Hoya fell to 38-5 with 30 KOs.
The 30-year-old Mayweather claimed before the bout that he would retire.
De La Hoya, 34, who last fought in May 2006 -- getting a sixth round TKO against Ricardo Mayorga -- is the only fighter to win world titles in six different weight classes.
He, too, has often talked about retirement.
Attkisson leaves CBS News, reportedly over network's 'liberal bias'
LGBT community has 'bullied the American people': Bachmann