The Clippers, who hope Leonard's return from a torn knee ligament will take them to a first NBA title, beat the 17-time champion Lakers for the eighth straight time.
Paul George scored 15 points and John Wall chipped in 15 in his first game for the Clips.
"It's amazing," Leonard said of playing on a full-strength Clippers team. "You see tonight, everybody is out there contributing on the defensive end and on the offensive end."
Leonard, who won titles with the San Antonio Spurs and Raptors, came off the bench for the first time since 2013 and played 21 minutes.
"I feel good," Leonard said, adding that coming off the bench wasn't a tough adjustment.
"I pretty much do my same routine, keep my focus and tell myself it's something that'll help in the long run," said Leonard, who entered the contest with six minutes left in the second quarter and promptly drained two shots.
For the Lakers, it was a second straight defeat to start the season, but coach Darvin Ham said he liked the fight he saw from LeBron James, Anthony Davis and company.
James finished with 20 points and 10 rebounds and Davis scored 25 points with eight rebounds despite hurting his back in a hard fall in the third quarter.
"We had a no-quit mentality," said Ham, whose assessment that the Lakers were "trending in the right direction" was echoed by Davis.
"Our competitive spirit was there," Davis said. "We did a good job on all their guys defensively. We've just got to do a better job of making shots."
Russell Westbrook had another nightmarish outing, scoring just two points on free throws as he went 0-for-11 from the field.
He did contribute defensively as the Lakers erased two sizeable deficits.
A 17-0 scoring run gave the Clippers a 15-point lead in the third quarter.
The Lakers battled back and took a two-point lead in the fourth quarter before the Clippers pulled away again.
James said it was an improvement on the Lakers' season-opening loss to the Golden State Warriors.
"We played the right way," James said. "I think we made another step forward today."
In the night's other match, the Bucks beat the 76ers 90-88.
