French rookie Wembanyama, who has produced a dazzling debut season in the NBA despite playing on a struggling Spurs team, was superb once again as San Antonio pulled off a remarkable victory over the reigning NBA champions.
The 20-year-old from Paris led an injury-hit Spurs line-up to finish with 34 points, 12 rebounds, five assists and two blocks, underscoring his reputation as the most exciting talent to land in NBA since LeBron James.
The result delighted San Antonio's veteran coach Gregg Popovich, who saw his team recover from a 23-point deficit early in the third quarter to snatch victory.
"Really proud of them, they played a great second half but they've done that all year - they don't give in," Popovich said of his team.
"Obviously with a lot of guys not there, we had a lot of people step up. Victor's Victor, he did a lot of good things, but it couldn't have happened without everybody else.
"Everybody contributed, they deserved it. They should all go get a beer, or a Coke, or whatever they do."
Denver meanwhile were left wondering where it all went wrong after 35 points from Jamal Murray and 22 points from Nikola Jokic.
Denver went into the game in Texas knowing that wins in their final two games would guarantee them top seeding from the West. However, the loss against the team that is bottom of the conference with a 21-60 record leaves everything hanging in the balance heading into Sunday's final regular season fixtures.
The Nuggets (56-25) are now third behind Oklahoma City, who pummeled the Milwaukee Bucks 125-107, and Minnesota, 109-106 winners over Atlanta.
Shai Gilgeous-Alexander scored 23 points while Chet Holmgren added 22 for the Thunder, who face a tricky final home game of the season against the Dallas Mavericks on Sunday.
Friday's results mean that leaders Oklahoma City, Minnesota and Denver are all level on 56-25, ensuring the race for top spot and home advantage will go down to the wire.
Elsewhere on Friday, Joel Embiid scored 32 points as the Philadelphia 76ers kept their bid for an automatic playoff berth alive in the Eastern Conference with a 125-113 victory over the Orlando Magic.
Orlando could have clinched a postseason berth with a win, but instead now face a nervous finale to the season on Sunday.
The Sixers have now won seven games straight in a late-season run that has coincided with Embiid's return from a two-month injury layoff.
The reigning NBA Most Valuable Player finished with 32 points, 13 rebounds and seven assists to shepherd Philadelphia to victory at the Wells Fargo Center.
Tyrese Maxey added 28 points while Kelly Oubre Jr finished with 21. Franz Wagner led the Magic scoring with 24 points.
In Cleveland meanwhile, the Cavaliers punched their postseason ticket with a 129-120 defeat of the Indiana Pacers.
A 70-point first-half performance set the Cavs on the way to victory, with Donovan Mitchell scoring 33 points and Jarrett Allen 24 from 11-of-12 shooting from the field.
Cleveland improved to 48-33 with the win to assure themselves of a postseason ticket.
Indiana meanwhile are locked in a three-way scrap with Philadelphia and Orlando heading into Sunday's final round of regular season fixtures. All three teams have identical 46-35 records as they chase the final two automatic playoff places.
In Boston, the top-seeded Celtics got back to winning ways with a 131-98 defeat of the Charlotte Hornets.
