The home side dominated the first half and went in two up, but it was only Brandon's strike 16 minutes from time that killed Hull off after they had fought hard to get back into the game.
Huddersfield's other goals came from Pawel Abbott, Rob Edwards and Andy Booth, while Danny Allsopp missed a late penalty for the visitors.
Town had the game won thanks to their first-half performance and took the lead in the seventh minute when Danny Schofield played in Andy Holdsworth, who crossed from the byline for Abbott to smash home first time.
Huddersfield should have had a second six minutes later when Brandon's deep cross was headed against the bar by Booth.
Abbott then saw his speculative drive from 35 yards drift wide before the Terriers deservedly doubled the lead in the 19th minute.
Hull's defence had at least three chances to clear but allowed Abbott to fire across the box. Brandon let it run and Edwards controlled the ball on his thigh and lashed a volley into the roof of the net.
After that Huddersfield eased off and allowed the visitors back into the game.
Hull continued that improvement after the break and substitute Jason Price hit the post after a scramble, before Leon Cort headed over when unmarked.
Brandon's goal came when Booth picked up on a loose pass and found substitute Junior Mendes, who set up Brandon with his first touch of the game.
Hull almost had a consolation after Steve Yates handled in the box eight minutes from time. Allsopp struck the spot-kick well but Ian Gray guessed the right way and pulled off a full-length stop.
Booth rounded off the scoring in the 87th minute with a brilliant turn and curling finish.
Even then there was still time for Mendes to break clean through and roll a finish narrowly wide.