Another inspirational display from MVP-candidate Harden included six rebounds and six assists as the Rockets delighted their home fans to improve to 53 and 14 at the top of the standings.
The Rockets now have a two-game advantage over the Golden State Warriors as the playoffs loom ever closer, meaning they are in pole position to retain home advantage through the postseason.
Harden was backed by 18 points from point guard Chris Paul, who had nine assists and three rebounds.
Injury-hit San Antonio, meanwhile, who have struggled in the absence of Kawhi Leonard and LaMarcus Aldridge, mostly failed to impose themselves on the Rockets defense.
Bryn Forbes and Derrick White led the scoring off the bench with 14 points each, while Rudy Gay was the leading scorer out of the starters with 13 points.
The loss saw the Spurs fall out of the playoff position in the Western Conference.
Gregg Popovich’s team are now in 10th place in the standings, and will need to arrest a steep dip in form if they are to avoid missing the postseason for the first time since 1996-1997.
The Spurs have now lost 11 of their last 14 games, and are in a real battle to make the playoffs in a crowded mid-table where only one game separates the teams placed seventh to 10th. The top eight teams reach the playoffs.
Elsewhere Tuesday, Russell Westbrook had a triple double as the Oklahoma City Thunder brought up their 40th win of the season in a 106-101 defeat of the Sacramento Kings.
Westbrook finished with 17 points, 10 rebounds and 11 assists as the Thunder improved to 40-29 to move up to fourth place in the Western Conference.
In the Eastern Conference, the Milwaukee Bucks cruised to a routine 121-103 win over the Memphis Grizzlies, staying in eighth place in the playoff seedings.
Khris Middleton had 24 points and Giannis Antetokounmpo 20. Brandon Jennings excelled off the bench with 16 points, 12 assists and eight rebounds.