New York's reserves outscored San Antonio's bench 54-38. Forward Steve Novak hit five of his seven three-point shot attempts for 15 points, and added two steals, while shooting guard J.R. Smith added 20 points and ignited the home crowd with an impressive reverse dunk.
The loss snapped San Antonio's seven-game winning streak.
New York led San Antonio 42-40 at halftime, and used an 11-0 run to jump out to a 17-point lead in the fourth quarter. The Knicks were helped by Carmelo Anthony, who led New York with 23 points and eight rebounds.
The Spurs shot just 36.4 percent from the field, and were out-rebounded 48-35, in an overall lackluster effort. Tim Duncan and Tony Parker each scored just 11 points, while Manu Ginobli converted just two of his 10 shot attempts for 10 points.
Thursday's contest was the fifth game the Spurs had played in the last seven days, and San Antonio appeared to be feeling the effects of playing back-to-back nights on the road.
"They shot the hell out of it and I could see it wasn't going to happen," said Spurs head coach Gregg Popovich, after the game. "Just too low on fuel, and their defense was too good -- bad combination. And then they made shots, which makes it worse."
"We played great tonight," said Knicks coach Mike Woodson. "We beat a damn-good ball club. It took a total team effort."
New York improved to 22-10, while San Antonio dropped to 26-9.