Huddersfield completed their second victory over Hull in the space of eight days to knock the Black and Whites out of the Challenge Cup.
Injury-hit Hull actually led 14-6 at half-time after home winger Tom Briscoe crossed twice.
But the Giants roared back after the break with two tries from winger Luke George and scores from Greg Eden, Leroy Cudjoe (2) and Joe Wardle.
Luke Robinson, Wardle and Jason Chan completed the second-half rout.
In the absence of nine regular first-teamers, Hull were forced to give a debut to three-quarter Ben Crooks, the 18-year-old son of former Hull and Great Britain forward Lee Crooks.
But it was Briscoe who opened the scoring, finishing off a neat cross-field move to touch down in the corner.
Huddersfield were exposed on the flanks for a second time when centre Jordan Turner once more sent Briscoe racing over.
But the Giants hit back when a handling error by scrum-half Brett Seymour put the visitors in a perfect attacking position and winger George took Kevin Brown's long pass to cross for his 11th try of the season.
Hull's lead was down to four within two minutes of the restart when George raced over for his second try.
The momentum was firmly with the Giants as full-back Eden was put through a gap by Danny Brough and had the pace to cross in the corner.
Cudjoe's spectacular long-range solo effort put the visitors ahead before Wardle ran 60 metres to score before Cudjoe added his second.
As Hull chanced their arm with the game slipping away, Huddersfield punished them further, hooker Robinson and second rower Chan adding tries.
VIEW FROM THE DRESSING ROOM
Hull coach Peter Gentle:
"I knew we were in trouble when I saw their team sheet with three NRL players on their bench.
"We're just depleted at the moment. The upside is the experience the young blokes are getting is terrific.
"Today we had to bring our best game with us and for 40 minutes I thought we did.
"I'm not disappointed. There was a lot of inexperience out there and we had a fair shot at them."
Huddersfield coach Nathan Brown:
"No side does anything without a good bench and obviously our bench was more experienced than theirs.
"We're fortunate that at the moment we've got a lot of blokes who have just come back from injury and it enabled us to have a bench that could have impact.
"You sort of expect Leroy Cudjoe to do that sort of thing, especially when the game is in the balance. He's a quality player. When you've got international centres in your squad, they are required to come up with big plays in big games.
"Physically, I thought we were average and they were quite good. We were behind the eight-ball but at least we maintained our composure and to score 40 points in the second half and keep them out was pleasing."
Hull: Lyne; Sharp, Martin, Turner, Briscoe; Ellis, Seymour; Moa, Houghton, Lynch, Manu, Tickle, Pitts.
Replacements: Green, Whiting, Kent, Crooks.
Huddersfield: Eden; McGillvary, Cudjoe, Wardle, George; Brough, Grix; Crabtree, Robinson, Gilmour, Lawrence, Chan, Brown.
Replacements: Faiumu, Fa'alogo, Patrick, O'Donnell.
Referee: Thierry Alibert (France).