After a comfortable start from the Championship promotion hopefuls, the visitors were gifted the lead when David Meyler terrible backpass allowed Olivier Giroud to slot home three minutes before half time.
The Tigers showed some signs of fighting back after the break, but conceded three goals in the final 19 minutes as Giroud volleyed in a second and Theo Walcott added a brace of his own.
For Hull fans, who were dreaming taking advantage of a faltering Arsenal side to pull off an upset, it was back down to earth with a bump as the gulf in class between two sides battling at the top of their respective divisions eventually became apparent.
There is growing concern amongst supporters of the Yorkshire club that they are in danger of throwing away their bid for automatic promotion, with the side having slipped out of the Championship top two, albeit with games in hand.
Steve Bruce's side appear to have hit a run of poor form, with the defeat against Arsenal meaning that they have won just two of their last eight matches in all competitions.
Unsurprisingly, it was Meyler who came in for the most criticism from the club's fans on Twitter after his mistake gifted the Gunners the advantage in what had until that moment been an even contest.
Can't believe that from Meyler. If there's one thing you can't afford to do against a team like Arsenal.... It's that. #hcafc— John Paul Fewster (@JpFewster) March 8, 2016
Bruce also came in for criticism from some sections of the club's support who were unhappy with the number of changes he made for the clash, with some accusing him of not caring about a potential lengthy cup run.
One squad rotation too many from Bruce. Extremely disappointing performance from #hcafc tonight— Chris Johnson (@JohnsonForza) March 8, 2016
We went into tonight's game not knowing who we'd be playing this weekend. It simply HAD to be worth having a go with a proper team. #hcafc— Matthew Rudd (@MatthewJRudd) March 8, 2016
I didn't expect to win but a home quarter final draw and that many changes?! Arse we there for the taking. Sorry but SB got it wrong #hcafc— Matthew Clarke (@Mattc1904) March 8, 2016
For some Hull fans, though, there were positive signs after the hosts held their own against their more illustrious opponents for the majority of the match.
Not a bad performance to be fair apart from a few brain farts, no point dwelling on it, let's tear MK Dons apart on Saturday! #hcafc— PW (@paulwyld) March 8, 2016
For others, however, this loss was just the latest defeat of an ever-concerning slump in recent weeks, which some fear is going to cost the club promotion.
Not worried about the 4 conceded, very worried about the nil scored. #hcafc - this season is over if we don't score goals very very soon.— Paul Dockerty (@pdockerty) March 8, 2016