Two days after falling to the Lakers in a game that James sat out, the Spurs halted the longest losing streak in franchise history.
Devin Vassell scored a career-high 36 points for San Antonio and seven Spurs players - including Wembanyama - scored in double figures.
Wembanyama, whose arrival in the league has been compared to that of James 20 years ago, scored 13 points and grabbed 15 rebounds with five assists, two blocked shots and two steals.
It was the rookie's fifth game this season with multiple blocks and multiple steals.
James, the four-time NBA champion who will turn 39 this month, scored 23 points with seven rebounds and 14 assists.
But without Anthony Davis, D'Angelo Russell and Cam Reddish the Lakers trailed from start to finish.
James impressed with an early steal and dunk, but the Spurs led by as many as 25 in the first half and for once were able to make the lead stand up.
Los Angeles cut the deficit to four points shortly before half-time with a run that included James's high-arching three-pointer over the towering Wembanyama.
But the Spurs kept the pressure on after the break, outscoring the Lakers 29-25 in the third period to take a 98-87 lead into the final quarter.
The Lakers pulled their starters midway through the fourth and the young Spurs team were able to celebrate their first victory since a November second triumph over Phoenix.
"This is what I'm addicted to, winning, this is what I love," said Wembanyama, who credited Vassell's 12-of-19 shooting with keeping the Lakers at bay.
"Everything went in," Wembanyama said of his teammate's big night. "I think if he didn't make those shots they would have had more runs, but by himself he kept the lead for us."
James said the multiple injury absences were just too much for the Lakers to overcome.
"You give credit where it's due," he added. "San Antonio played great tonight, they shot the ball extremely well. They attacked us and we're just limited with bodies."
James said his first clash with Wembanyama only reinforced his previous assessment that the highly touted rookie is a "special talent".
There was no respite for the Detroit Pistons, who suffered a franchise-record 22nd straight defeat with a 124-92 loss to the 76ers in Philadelphia.
Philadelphia's NBA Most Valuable Player Joel Embiid scored 35 points and pulled down 13 rebounds for his ninth straight double-double.
Tyrese Maxey added 19 points for the Sixers, who won their fifth straight.
The Pistons had matched their longest-ever losing streak with a loss to Philadelphia on Wednesday.
Their skid is the sixth-longest in a single season in NBA history. Cleveland in 2010/11 and Philadelphia in 2013/14 share the record for the longest at 26 straight defeats.
Brunson pours in 50
New York's Jalen Brunson made nine of nine from three-point range on the way to a career-high 50 points in the Knicks' 139-122 victory over the Suns in Phoenix.
Brunson was a perfect 12-for-12 from the floor in the second half - including eight three-pointers - as the Knicks handed the Suns a defeat made more painful by the early exit of Bradley Beal with an ankle injury.
The Eastern Conference-leading Boston Celtics remained unbeaten at home, riding 30 points from Jayson Tatum to a 128-111 victory over the upstart Orlando Magic.
Derrick White added 19 points, Jaylen Brown scored 18 and Payton Pritchard added 21 off the bench for the Celtics, who improved to 13-0 at TD Garden and 19-5 for the season despite missing Kristaps Porzingis, Al Horford and Luke Kornet.
Jalen Suggs scored 19 points for the Magic, who dropped to fourth in the East behind the Celtics, Bucks and 76ers.
Dillon Brooks made a triumphant return to Memphis, scoring 24 of his 26 points in the second half to fuel the Houston Rockets' rally for a 103-96 victory over the Grizzlies, who traded Brooks in the offseason.
