Lillard, averaging 18 points a game in his first NBA campaign, scored 29 points while adding seven rebounds and seven assists.
The Trail Blazers opened a 12-point lead in the third period and held on to win their second in a row.
After capturing 18 of its first 22 games this season, San Antonio has now lost twice in as many nights. The Spurs suffered a three-point setback against Utah on Wednesday.
Lillard made 11-of-22 shots from the field and all five of his free throws. His previous high game had been 28 points, delivered against Minnesota on Nov. 23.
LaMarcus Aldridge added 22 points for Portland and J.J. Hickson had 12 points and 12 rebounds.