The first overall pick in last year's draft rattled up his career-high 50 points in just 26 minutes and ended the game with 18-29 shooting with eight three-pointers -- also a career high.
The Spurs center, whose previous highest-scoring game was 40, was at a loss to explain his incredible performance.
"I'd love to tell you that you wake up a certain way or you feel really smooth during warm-ups, but at the end of the day, in NBA games we got one game every other day," he said.
"So every time we struggle to warm up, we have pain, you know, we sweat, we bleed on the court, so it's really a minute-to-minute thing, it comes to 48 minutes every game," he added.
It was the third straight game in which Wembanyama had hit six-plus three-pointers.
The three players who scored 50 points at a younger age than the Frenchman were Brandon Jennings, LeBron James and Devin Booker, all of whom were also aged 20.
The Spurs again won the game without head coach Gregg Popovich. The team said on Wednesday that he had suffered a mild stroke earlier this month but is expected to make a full recovery.
Wembanyama wasn't the only player to break the 50-point mark on Wednesday. Giannis Antetokounmpo scored 59 as the Milwaukee Bucks beat the Detroit Pistons 127-120 in overtime.
The Greek star shot 21 of 34 and had 14 rebounds and seven assists in what was the highest point performance by a player so far this season.
"As a leader I keep reminding guys, don't take moments for granted. No matter who plays we don't give up and always have to find ways to win the game," said Antetokounmpo.
Cavs roll on
The unbeaten Cleveland Cavaliers made it 13 straight wins in the NBA with a 114-106 victory at the Philadelphia 76ers.
With the win the Cavs became just the sixth team to start a season with a 13-0 record and the first since the Golden State Warriors in the 2015-16 season.
Darius Garland top-scored for Cleveland with 25 points while Donovan Mitchell put up 23 points along with nine assists and 13 rebounds.
Mitchell ended the game on fire, scoring 11 points in a 1:35 spell in the fourth quarter.
Cleveland trailed 54-48 at the half but turned it on in the third quarter. Yet it was a tight game until Mitchell made a 29-foot three-pointer with 2:52 remaining to open up a seven-point lead.
Mitchell conceded that the 13th game in 22 days had been a battle.
"We all fought. Biggest thing is, obviously, we played a lot of games and it's going to test you.
"The streak is going to test you. These games are going to test you.
"We kept pushing, just continued to fight, continued to battle and we all did a great job," he said.
Philadelphia's injury-plagued star center Joel Embiid, who made his first appearance of the season on Tuesday after nine games out with a knee issue, sat out the game and the 76ers were also without Paul George.
Rookie Jared McCain stepped up with 34 points for Philadelphia, who are 2-9 on the season.
The Boston Celtics continued their strong start to the season. Their 139-114 win at the Brooklyn Nets extended their record to 10-3.
Jayson Tatum put up 36 points, made 10 assists and grabbed eight rebounds as the reigning champion Celtics enjoyed a convincing victory.
After a defeat to Atlanta in the NBA Cup on Tuesday, the Celtics trailed by two after the first quarter but grabbed a five-point lead by the half and dominated from then on.
It was a strong all-round display from Boston with Jaylen Brown producing 24 points and 12 rebounds while Payton Pritchard claimed 23 points and had eight assists and six rebounds.
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