The reigning NBA MVP reached at least 30 points for the 17th successive game – the best such run since Wilt Chamberlain in 1964 – and had done so by half-time at Toyota Center.
He had 36 points on the board by the end of the second quarter and continued his onslaught after the resumption before finishing with his best haul of the campaign to date.
And in another piece of history-making, Harden broke a franchise record by scoring more than 40 points for the 14th time this season.
In response to Harden's points avalanche, Memphis' best return was the 14 points recorded by Garrett Temple and Mike Conley as the Grizzlies fell to an eighth loss in nine games.
Tony Parker enjoyed a successful first return to San Antonio since moving to Charlotte last summer as the Hornets claimed a 108-93 victory over the Spurs.
Kemba Walker top-scored with 33 points and Parker – who helped San Antonio win four NBA titles in a 17-year stay – added eight points, four assists and three rebounds to end a three-game losing streak for the Hornets.
D'Angelo Russell mounted a monster third-quarter rally, scoring 18 of his total 34 points to push the Brooklyn Nets to a 109-102 win over the Boston Celtics.
Brooklyn's triumph snapped a 10-game losing streak to Boston, who were still without injured Kyrie Irving.
In Los Angeles, the Clippers suffered a home defeat to the New Orleans Pelicans, who triumphed 121-117 after Anthony Davis dished out 46 points and grabbed 16 rebounds.
Elsewhere, the Utah Jazz claimed their sixth win in seven games with a 100-94 victory over the Detroit Pistons and the Sacramento Kings extended their winning run to three games, beating the Portland Trail Blazers 115-107.