Bryant had nine turnovers and scored just 11 points as the Lakers produced their lowest scoring total of the season.
The win also ended the Thunder's 12-game losing streak to the Lakers. They had not beaten the Western Conference's top team since 2006.
"We're growing up," forward Kevin Durant, who had 26 points, told reporters. "We're maturing as a group throughout the season and I think it was a good job of showing that tonight."
Russell Westbrook added 23 for the Thunder, who rank sixth in the Western Conference playoff race behind the leading Lakers.
Oklahoma City coach Scott Brooks credited guard Thabo Sefolosha's aggressive defensive play for Bryant's off night.
"If you're going to be considered one of the better defenders you have to guard the best players," Brooks said.
"You can't get your feelings hurt when you get scored on and Thabo doesn't. He wipes it away and comes back next possession with great energy and great effort."
Bryant had five turnovers in the first quarter and was just four-of-11 shooting for the game.
"They did a great job defensively, it was a team effort and they did a great job executing their game plan," Bryant said.
Oklahoma City (44-27) set the game's tone with a 13-4 run to start play and built the lead to 53-34 at the half.
Center Nenad Krstic and Westbrook also played big roles in the quick start.
Westbrook scored 13 points in the opening quarter, and Krstic grabbed nine of his game-high 10 rebounds.
"He (Krstic) really controlled the paint on the defensive rebounds there," Brooks said.
Lakers big man Pau Gasol finished with just nine points.
A 16-2 spurt to close the third quarter put the Thunder in front 80-47.
"We never bragged or never got into the crowd," Durant said of the streaks. "We just got back on defense and we were locked in on the defensive end. It showed that we were getting better."
(Reporting by Gene Cherry in Salvo, North Carolina, edited by Patrick Johnston)