Standoff Chris Thorman scored a try and kicked seven goals to top 1,000 career points as the Giants won for a record fourth straight Super League game.
Thorman's touchdown on 49 minutes was the game's best effort, with Chris Nero breaking from deep to set up Stephen Wild for a charge forward and Thorman finishing off in style near the posts.
It was the second converted try the Giants scored while the visitors were down to 12 men following the sin-binning of Lee Hopkins in first-half overtime and gave Huddersfield a comfortable 32-10 cushion.
Thorman, in inspirational form throughout, also helped set up two tries in two minutes later in the second half to put the result beyond doubt.
Nero and Paul Reilly dived over on 58 and 60 minutes to add to a Wild double and a try from Steve Snitch as the Giants quickly racked up 26 points in a dominant second half display.
It was a far cry from the opening period - Harlequins were 10-6 ahead at one stage thanks to tries from Chad Randall and Tyrone Smith.
Jamahl Lolesi got Huddersfield off to a flying start with the game's opening score from Stuart Jones' final pass on six minutes. But the visitors dominated after that and were deservedly in front until Reilly scored and made another for Snitch just before half time.
The sin binning of Hopkins proved the difference in the second half. Harlequins were hardly in contention and it took until two minutes from time for ex-Giants star Jon Grayshon to grab a consolation try for the visitors.
The Giants, who had lost their opening seven Super League games, now look like an unstoppable force. They have won all five of their previous outings, including a 74-4 Challenge Cup thrashing of York.