The Houston Rockets guard, who amazingly is still just third in voting for the Western Conference All-Star backcourt, scored 57 points to break Kobe Bryant's consecutive games record of scoring at least 30 in his team's 112-94 win over the Memphis Grizzlies.
Harden had 36 points before halftime.
The Monday matchup is the first the team is facing this season without Chris Paul, Eric Gordon and newly-injured Clint Capela.
Harden's total is three points shy from his own Rockets single-game record of 60 that he set last season. In fact, Harden owns four of the top six highest single-game scoring totals in franchise history.
The win also notches head coach Mike D'Antoni's 600th career victory.
Danuel House Jr. scored 15 points. Gerald Green added 14 points off the bench.
Nene, who took up the starting role for Capela, played just 14 minutes.
Houston (25-18) hosts Brooklyn on Wednesday.
Let's start with the positives. The Houston Rockets have an outstanding 17-game stretch in which they got away with 14 wins.
In addition, the team went 8-3 in the games after losing Chris Paul to a thigh injury vs. Miami. Much of the momentum is being attributed to James Harden's outstanding case to repeat as NBA MVP.
But, much of that stretch takes into account the contributions of Clint Capela, who has been the typical rebounding and inside scoring machine for Houston.
Capela will miss an estimated four-to-six weeks with a thumb injury. The first opponent for the Rockets without Paul, Capela and Eric Gordon is the Memphis Grizzlies, who come into Toyota Center just five games back from Houston in the Southwest Division.
Capela's loss further deepens the Rockets' margin for error in the tight Western Conference. Despite leading the division, they are the sixth seed heading into Monday, and a bad stretch could put them out of the top eight.
Still, the Rockets may as well lean into small ball in their revamped lineup. Nene, who at 36 has played every other game of the season, takes up starting center duties in place of Capela. In a corresponding move, the Rockets recalled 7'1" big man Isaiah Hartenstein from the RGV Vipers.
Houston has already won two of its matchups with Memphis this season.
Already down CP3, Rockets reportedly lose Capela due to thumb injury