Hopkins drilled De La Hoya with a hard left hand just below his rib cage, and De La Hoya crumpled to the canvas, the Chicago Tribune reported.
He was gasping for breath as referee Kenny Bayless counted him out at 1:23 of the ninth round.
De La Hoya had never been knocked out in 12 years as a professional boxer.
"Oscar was boxing a good boxing game, but I knew I was in control," Hopkins said. "It was a great body shot. I heard the wind come out of him."