In a fight expected to be one of the highest-grossing in boxing history, Mayweather won a tight verdict from two of the three judges to improve his career record to 38-0 with 24 knockouts.
The 30-year-old American, widely regarded as the world's best fighter pound-for-pound, defended skilfully early on before imposing himself in the later rounds with his powerful right, his speed and several telling combinations.
Mayweather connected with a thumping right and left early in the 12th and final round before a flurry of close-range punches from both fighters ended the bout in front of a capacity crowd of 16,200 at the MGM Grand Hotel and Casino.
"I was having fun in there," a jubilant Mayweather told reporters after winning a world title in his fifth weight division. "It was a hell of fight but it was easy work for me. He threw a lot of punches but they weren't landing.
"I could see the shots coming. I stayed on the outside and made him miss. He's the best fighter of our era and I beat him.
Mayweather was favoured by the official ringside statistics, connecting with 207 of 481 punches thrown to 122 of 587 for De La Hoya. He also landed 138 power punches compared to De La Hoya's 82.
"Now I am going to retire," added Mayweather, who climbed into the ring at the start of the fight wearing a Mexican sombrero, a cheeky reference to his opponent's heritage on Cinco de Mayo.
NOTHING TO PROVE
"I don't have anything else left to prove. I want to spend more time with my children."
Fan favourite De La Hoya, arguably the biggest name in boxing despite being in the twilight of his career, was the aggressor for most of the fight, earning as many cheers as Mayweather received boos.
He started impressively by pinning Mayweather against the ropes and frequently connecting with his trademark left hook.
However, the 34-year-old Mexican-American found it increasingly difficult to penetrate Mayweather's renowned defense and his close-range jabs became more ineffective.
"I felt I won," De La Hoya said after one of the judges gave him the fight by 115 points to 113. Mayweather gained the other two verdicts 116-112 and 115-113.
"I felt I landed the harder, crisper punches," De La Hoya added. "When I landed my punches, I could see I was hurting him. I was pressing and wanted to stop him. I was trying to close the show.
"I am the champion and you've got to do more than that to beat the champion. It was not the best night for my jab. It was working but I couldn't throw it."
De La Hoya, who has lost five of his last 12 bouts, held the upper hand in the early rounds as the atmosphere in the arena became electric.
MAINTAINED INITIATIVE
Trying to cramp his opponent, he maintained the initiative with a flurry of left hooks, one of them connecting with Mayweather's head in the second round.
He upped the tempo in the third round, pinning Mayweather against the ropes with a series of close jabs and punches. Although Mayweather responded with a probing overhead right, De La Hoya retained overall control.
Two early left hooks by De La Hoya set the tone for another dominant performance in round four.
With Mayweather on perpetual retreat, the champion again forced him into the corner and pummelled his left side with a series of jabs. De La Hoya unleashed another powerful left hook just before the bell.
Mayweather connected with an overhead right early in round five before De La Hoya responded with a flurry of close jabs. Mayweather began to find his range and dominated the rest of the round with a series of solid blows to De La Hoya's head.
The momentum stayed with Mayweather for the rest of the fight. Although De La Hoya frequently backed his opponent into the ropes, very few of his jabs and punches landed because of Mayweather's skilful ducking and weaving.
De La Hoya was rocked by a Mayweather right late in the final round before the two fighters traded punches in a furious finish with most of the crowd on their feet. After the bell sounded, the two protagonists embraced each other.
The much-hyped showdown at the MGM Grand arena was broadcast to 176 countries, with total revenue predicted to exceed $100 million.
