Harden, the league's scoring leader at 32.1 points per game, injured his left hamstring while driving for a layup late in the fourth quarter of Houston's double-overtime victory over the Los Angeles Lakers on Sunday.
Harden's absence comes soon after the Rockets, who snapped a five-game losing streak with Sunday's win, had two starters return from injury. Houston went 0-3 while guard Chris Paul recovered from a strained left adductor. Center Clint Capela missed all but one game of the five-game losing streak due to a bruised left heel and right orbital fracture.
Harden, who also ranks third in the league with 9.1 assists per game, has been durable throughout his career. He has missed a total of only two games since the start of the 2014-15 season and has never missed more than nine games in a season.
Houston (26-9) is in second place in the Western Conference, two games behind the Golden State Warriors. The Rockets are 15-2 when Harden and Paul play together, with Paul missing a total of 18 games due to injuries.
Harden was the MVP runner-up last season for the second time in his career and has established himself as one of the front-runners for the award this season. His scoring average has jumped more than three points per game after he also led the league last season, and he is having his most efficient shooting season (.627 true shooting percentage) in his six years of being the Rockets' go-to guy.
While Harden expressed optimism in the immediate aftermath of his injury Sunday, his teammates acknowledged it would be challenging if he were to miss time.
"Yeah, we lost our horse," Paul said.
Said forward Trevor Ariza: "If James misses time, it is going to be tough. Since I have been here, he's been here, he has been on the court, he has been available. So for him to have to miss time, it would definitely be tough, definitely be an adjustment."
ESPN's Ohm Youngmisuk contributed to this report.