Bryant, who had missed the previous seven games with a bruised left shin, scored 18 points on 7 of 12 shooting.
The Lakers went 5-2 without the NBA's scoring leader, but with only two games left in the regular season for Los Angeles, Bryant returned as he aims to get into a rhythm before the playoffs begin.
Bryant wore a black sock over his lower left leg, with a padded sleeve protecting the injured area. While the Spurs said after the game that he's not the old Bryant just yet, he's not so sure.
"I'm back now," Bryant said. "It took me a half. The second half, it felt like I was back in a good rhythm. The game just got away from us."
The Spurs (46-16) won their sixth straight game and remain a half game ahead of Oklahoma City for the No. 1 seed in the West. The Lakers (40-24) missed a chance to clinch home court in the first round of the playoffs.
These teams could meet in the opening round, and judging by their latest meeting, it would be a mismatch.
San Antonio has given Los Angeles its two worst losses of the season, Friday night and 112-91 on Tuesday. Duncan had 21 points and eight rebounds, Parker had 20 points and 10 assists and Ginobili added 20 points and seven assists on Friday.
San Antonio broke the game open in the third quarter, when Bryant played his best. The Lakers' star hit 5 of 6 shots in the quarter, directing his teammates on offense and yelling at them to "D-up" on defense.
It hardly mattered, though, as he repeatedly was on his heels on defense as the Spurs pushed the ball. San Antonio outscored Los Angeles 35-21 in the quarter.
"They did a great job spacing the floor," Bryant said. "As a result, our defense was always late. It was always playing catch up on possessions. They did a great job shooting the ball. They did a great job on close outs. They played extremely well."
While Bryant was sidelined, several Lakers increased their scoring, none more than Metta World Peace. World Peace more than doubled his scoring average with Bryant out of the lineup, but he had only 10 points on 3-of-9 shooting against the Spurs.
The Lakers have little time to transition Bryant back into the system before the postseason, but Parker has been around long enough to expect the best from him.
"Yeah, he looked a little bit rusty," Parker said. "It's going to take some time. But I'm not worried about him. He'll be ready when the playoffs start."
Bryant isn't worried facing the Spurs in the playoffs, despite the recent blowouts.
"Nah, listen. This team, (coach Gregg) Popovich, the experience that they have, the adjustments that they make, it is going to happen every now and then," Bryant said. "But you have to make adjustments. If we're fortunate to see them in the postseason, we'll make our adjustments defensively."
Kawhi Leonard, a rookie who was drafted largely for his defensive ability, started the game guarding Bryant. Popovich said before the game that it was time for his young players to see "the real thing." Bryant quickly gave Leonard a taste, taking him down low and burying a shot over him while getting fouled. Bryant hit the ensuing free throw, but he didn't score again until he hit a 15-foot jumper with 34 seconds left in the quarter.
"He did well," Duncan said of Leonard. "It's a learning process obviously, and Kobe got him with some vintage stuff and some and-ones. But Kawhi is a quick learner, very long and a very good defender. If we have to see him again, I think the experience is great for him."
Seven-time Tour de France champion Lance Armstrong sat courtside. ... The Spurs hit 10 of 15 3-pointers for a season-high 66.7 percent. ... Lakers G Devin Ebanks, who started with Bryant out, played only 8 minutes and didn't score. ... Spurs C Tiago Splitter started and DeJuan Blair came off the bench against the tall Lakers' frontline. Splitter is 6-foot-11, and Blair is 6-7. ... With Magic C Dwight Howard possibly out for the Summer Olympics after electing to have back surgery, Bynum looks like a possible replacement. "It's the same thing for any coach who has a player playing," Brown said. "Rest, rest, rest. You worry about the injuries, but at the end of the day, it's a significant honor."