Nick Proschwitz was the hosts' hero, firing home on the hour to secure Hull's progression into the last 16 for the first time since the 1977-78 season.
Huddersfield had beaten Bradford City and Charlton Athletic in previous rounds, but never really looked like adding a Premier League scalp at the KC Stadium.
Following impressive starts to their respective league campaigns, both sides used the tie to give their squad players a chance to impress.
Hull manager Steve Bruce made nine changes to the side that won away at Newcastle United on Saturday, with only Liam Rosenior and Stephen Quinn retained in the starting line-up.
Huddersfield boss Mark Robins went one better than his former Manchester United team-mate Bruce, with goalkeeper Alex Smithies the sole survivor from their goalless draw at Blackburn Rovers over the weekend.
The away side started brightly and had the first effort on goal after just three minutes, although Keith Southern failed to test veteran goalkeeper Steve Harper.
The home side became more dominant as the half wore on and returning striker Matty Fryatt had two great chances within a minute to give them the lead just before the half hour.
First he struck the post from 10 yards out after being played in by Proschwitz, before firing another effort over the crossbar just seconds later.
Hull had a further chance just before the break, but Yannick Sagbo curled his shot over following a Proschwitz knock-down after 43 minutes and the game remained all square at half-time.
Sagbo was again the first to threaten in the second period, but his speculative volley from distance failed to trouble Smithies.
The game was desperate for a spark and it arrived on the hour mark through the impressive Proschwitz.
The giant German striker, signed for £2.6 million from SC Paderborn 07 in July last year, made the most of his recall by thumping the ball past Smithies after George Boyd had flicked the ball on.
Abdoulaye Faye nearly doubled the lead after 73 minutes, but his towering header from Boyd's corner fell just past the far post.
Huddersfield could not convert their spells of possession into clear-cut chances and Harper was allowed a quiet evening in what was the first meeting in the League Cup between the two sides.
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