Tony Parker scored 24 points on 12-18 shooting to lead San Antonio to a 2-0 start on the season.
The Lakers lost their first game at home, and second in a row to fall to 1-2.
Pau Gasol led the Lakers with 20 points and 11 rebounds as the team shot just 36.3% from the field. The Lakers missed 19 three-point attempts on 27 tries (29.6%).
Earlier in the game, the Lakers had a 15-point lead but it quickly disappeared after Xavier Henry sustained a forehead laceration in the first half that required nine stitches.
Henry later returned but scored just three points in 21 minutes, missing all six of his shot attempts.
The Spurs took a six-point lead in the third quarter, before the Lakers scored two final baskets including a buzzer-beating layup by Jodie Meeks.
Turnovers, missed layups, missed free throws, missed dunks -- it was not a pretty quarter of basketball.
The Lakers shot just 35% through 36 minutes. The Spurs slightly higher at 37%.
The Lakers extended their lead to 15 against the Spurs in the second quarter.
The momentum shifted after Xavier Henry took a hard fall, driving to the basket. He sustained what looked like a contusion to the forehead that bled profusely. After the training staff attended to him for a number of minutes, Henry stepped to the line to convert to free throws.
The Lakers called for time the next play, allowing Henry to run to the locker room — for stitches and maybe even a concussion test. Henry was back on the bench before halftime.
The Spurs resumed with renewed energy, closing the gap to a single point by the half.