In what was a questionable decision, De la Hoya threw and landed considerably more punches, but lost, 115-113, on the scorecards of all three judges at the MGM Grand Hotel and Casino in Las Vegas.
"You never know what is going to happen when it is handed to the judges," Mosley said. "Anything can happen. De la Hoya is a great warrior. I thought it was a close fight."
All three judges gave the final four rounds to Mosley, who landed more telling blows in that span.
De la Hoya, 30, was hoping to avenge one of his two losses as a professional, but instead was left with memories of the other defeat, a controversial 12-round loss to Felix Trinidad in September 1999 that cost him his WBC welterweight belt.
"It happened to me in the Trinidad fight, and it happened to me here," de la Hoya said. "I thought I did enough. Shane told me, 'I thought you had a draw.'"
In the fourth round, an accidental head butt opened a cut at the edge of de la Hoya's right eye.
De La Hoya plans to hire lawyers on Monday to investigate the decision.