Harden scored 37 points, including 17 in the third quarter, and the Rockets led from wire-to-wire in a 118-111 victory on Saturday night.
With Howard out for a third straight game because of a sore left ankle, Harden provided a boost. He was 9 of 15 from the field, hit five 3-pointers, made all 14 of his free throws and had 11 assists without playing the fourth quarter after Houston built a 29-point lead late in the third.
"Great players do that, they get going," Rockets coach Kevin McHale said. "I've seen James do it countless times, but that's what separates him from a lot of players. He has the ability to do that."
Harden dominated in just about every aspect of the game. He drove to the basket, buried shots from well beyond the 3-point line, converted free throws and found open teammates.
"I just tried to be aggressive and be in attack mode to get to the rim," he said. "If the drive is there, I take it. If it's not, I'll do something else. I just use my basketball instincts."
Cleveland has lost four straight and played again without point guard Kyrie Irving, who has been sidelined for three games with a strained left biceps.
Houston made its first four shots and took a quick lead in snapping a three-game road losing streak. The Rockets also strengthened their hold on the fourth spot in the Western Conference playoff race.
The Rockets played their reserves for most of the fourth and Cleveland cut into the margin.
Harden had eight points and eight assists in the first quarter, which saw Cleveland coach Mike Brown call timeout twice in the first four minutes as Houston took a 17-4 lead.
The margin reached 15 points in the second period and Houston shot 59 percent in the first half.
Cleveland scored the first seven points of the third quarter to cut the lead to 67-62, but Harden's five free throws sparked a 9-0 run and the Rockets regained control. His four-point play pushed the lead to 87-70.
Harden hit a 3-pointer from the top of the key moments later, then added a dunk and another 3-pointer as the lead reached 101-72.
"Obviously, Harden had a monster game," Brown said.
Howard returned to practice Friday and participated in Saturday morning's shootaround, but didn't dress for the game. He played in each of Houston's first 66 games, but was a late scratch Monday, had a cyst removed from the ankle the following day and didn't play Thursday.
"I don't think he feels quite good enough to play, but he feels much better," McHale said before the game.
Houston is undefeated in the eight-time All-Star's absence. Howard scored 26 points and had six rebounds in the Rockets' 106-92 win over Cleveland on Feb. 1. He averages 18.6 points and 12.4 rebounds for the season.
Injuries and a brutal schedule have dropped Cleveland out of playoff contention. The Cavaliers are 2-8 in March and trail Atlanta by 6 1/2 games for the eighth spot in the Eastern Conference. Cleveland, which has also dropped games to the Los Angeles Clippers, Miami and Oklahoma City in the streak, has lost eight of 10 and has dropped five straight at home.
The Cavaliers fell behind by 24 points in Thursday's loss to the Thunder, a trend Brown is displeased with.
"That's two games in a row that we've come out and our first group has just been flat," he said. "They've been flat offensively, flat defensively. So it's been an uphill battle, especially being short-handed."
The difficult schedule continues Sunday when the Cavaliers travel to New York, which has won eight in a row. Cleveland was routed 113-86 on Jan. 30 at Madison Square Garden.
The Rockets have won four straight and six of their last seven against the Cavaliers.
Seth Curry, signed by Cleveland to a 10-day contract Friday, scored three points in eight minutes. He's the younger brother of Warriors star point guard Stephen Curry.
NOTES: Rockets guard Francisco Garcia isn't with the team because of personal reasons. ... In addition to missing Irving and Deng, the Cavaliers played without guard C.J. Miles (sprained left ankle) and forwards Anthony Bennett (strained left patellar) and Sergey Karasev (sore right knee). ... Seth Curry appeared in one game earlier this season for Memphis, playing four scoreless minutes. ... Houston plays at Charlotte on Monday.