French prodigy Wembanyama - playing after a 12-game absence following a month-long injury layoff - led a superb performance from the Spurs to send Oklahoma City crashing to just their second defeat of the season.
Reigning NBA champions Oklahoma City, who had gone into the game on the back of a 16-game winning streak, looked to be surging into Tuesday's final against the New York Knicks after going 16 points up in the second quarter.
But the towering 7ft 4in (2.24m) Wembanyama led a relentless fightback from San Antonio, dominating at both ends of the court, to set up a pulsating victory.
Wembanyama started on the bench and sat out the first quarter, but made a huge impact when he was brought in for the second.
The 21-year-old's 22 points, nine rebounds and two blocks came from just 21 minutes on court.
"I knew I had limited minutes so I had to make the most out of it," Wembanyama said.
"Winning against a team like this, it might seem like it's just a game but it's a collective effort and it's not an easy thing.
"It's only their second loss of the season. It means something."
Wembanyama was one of four San Antonio players to finish with double figures, with Devin Vassell scoring 23, and Stephon Castle and De'Aaron Fox adding 22 apiece.
"There were three or four guys who scored over 20 in our team. It just shows that everybody was involved," said Wembanyama.
"It says a lot. And it says a lot about where this team is going to be in the future," he said.
"This NBA thing: one thing to understand is that it will test your limits. And right now I've just come off 12 games' rest, so I'm fresh."
Reigning NBA Most Valuable Player Shai Gilgeous-Alexander led the Thunder scoring with 29 points, while Jalen Williams and Chet Holmgren added 17 points each.