The Thunder came storming back in the third quarter, coming from an 18 point deficit to take a lead as Russell Westbrook started to showcase his influence.
Westbrook would end with 27 points, six rebounds and 14 assists, but went scoreless in the final quarter as the Spurs pulled away thanks to Kawhi Leonard and LaMarcus Aldridge.
The duo were the only two players to score double digits for the Spurs, with Leonard dropping 36 points, eight rebounds, four assists and two blocks, while Aldridge added 25 points, six rebounds and three blocks.
Spurs coach Gregg Popovich claimed his 1,126th career victory, leaving him just one short of tying the league record for most wins with one franchise, which is held by former Utah Jazz coach Jerry Sloan.
The Spurs are now 37-11, while the Thunder drop to 28-21 to sit seventh in the Western Conference.
The Thunder are back in action tomorrow against the battling Chicago Bulls.