Wembanyama, whose California swing will include a second All-Star Game appearance on Sunday, added 12 rebounds, two steals and a blocked shot, connecting on 13 of 20 attempts from the field in his 26 minutes of work.
The Lakers were without a raft of starters, with LeBron James and Luka Doncic sidelined along with Austin Reaves and Marcus Smart.
Doncic missed a third straight game with a hamstring strain. James sat out the second night of a back-to-back to manage foot arthritis.
Wembanyama took full advantage, setting the tone with 25 points in just eight minutes on the floor in the first quarter.
He had 37 by halftime - the most by any player in a first half this season - when the Spurs led 84-55.
He cooled off in the third quarter, but matched the 40 points he put up on opening night before sitting out the fourth period with the rest of the Spurs starters.
The only down note for the Spurs was an injury to 2025 Rookie of the Year Stephon Castle, who took a hard fall under the basket in the second quarter and exited with a pelvic contusion.
Siakam shines
The Indiana Pacers, fueled by 30 points from Pascal Siakam, stunned the New York Knicks 137-134 in an NBA overtime thriller at Madison Square Garden on Tuesday.
Eight Pacers players scored in double figures to bring home the win in a game that featured a season-high 39 lead changes.
Andrew Nembhard added 24 points and 10 rebounds, and Quenton Jackson scored 19, including two game-sealing free throws with 3.9 seconds left in overtime.
Jalen Brunson scored 40 points with five rebounds and eight assists for the Knicks. Josh Hart chipped in a triple-double of 15 points, 11 rebounds, and 11 assists.
Mikal Bridges and Karl-Anthony Towns added 22 points apiece - Towns drilling two free throws to force overtime before fouling out in the extra session.
The Pacers scored the first nine points in overtime before the Knicks staged a furious rally, cutting the deficit to one on a three-pointer from Brunson before Jackson closed it out at the line.
The Pacers have been a shadow of the team that beat the Knicks in the Eastern Conference finals last season, with Tyrese Haliburton sidelined by the ruptured Achilles tendon he suffered in their NBA Finals loss to Oklahoma City.
But they snapped a four-game skid with just their fourth road win of the season, this one against a Knicks team that came in tied for the second-most home wins in the league with 21.
"This was a really important game for us," said Pacers coach Rick Carlisle. "The season that we've had, this environment, the opponent - our guys had a great collective spirit and collective will tonight."
It was a big comedown for a Knicks team that slipped half a game behind the Boston Celtics into third place in the East, six games behind conference leaders Detroit.
They had won nine of their past 10 games, with seven of those wins coming by double digits.
Around the league
In Houston, Kevin Durant scored 26 points to lead the Rockets to a 102-95 victory over the Los Angeles Clippers.
Down by one at halftime, the Rockets took control in the third quarter. They led by six going into the fourth and quickly pushed the lead to 15 to cruise home.
Kawhi Leonard scored 24 points to lead the Clippers. John Collins added 17, and Bennedict Mathurin contributed nine off the bench in his Clippers debut.
Darius Garland, also acquired at the trade deadline in a deal that sent James Harden to the Cleveland Cavaliers, remained sidelined by a toe injury.