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.