It was the second hammering Town had suffered at the New Stadium this season having been whipped 5-0 in the league on August 29.
Emlyn Williams side will take on Huws Gray Alliance newcomers Llanrhaeadr full of confidence having won nine league and cup matches in a row, on the way scoring 42 goals.
Last Saturdays Cookson tie was a niggly affair spoiled somewhat by an over-zealous referee who dismissed Denbighs Seb Walker with 15 minutes left and cautioned five Hotspur players.
Holyhead should have opened their account in the fifth minute when Jay Gibbs and Mel McGinness combined to set up Asa Thomas who somehow fired over a gaping goal.
Mark Roberts forced home keeper Ben Heald into a good stop and visiting glovesman Arwel Hughes did well to deny Mike Edwards.
The islanders took the lead on 11 minutes when Edwards drilled the ball into the area and defender Alex Jones found the far corner of the net.
Stuart Vernon had a chance to level it but the home defence pulled off fine blocks, then Hotspurs Thomas sent a lob agonisingly wide.
The Anglesey aces added a second before the break, though, when McGinness strike was well saved by Hughes, but this time Thomas made no mistake to plunder his 12th goal of the campaign.
Hughes twice prevented McGinness stretching the home lead before the interval.
After the turnaround Holyhead stayed in the ascendency and extended their advantage on 59 minutes when the previously impressive Hughes let his standards slip as a Mike Edwards shot from 15 yards squirmed in under the keepers body.
McGinness deservedly got in on the act with his 12th of the season when he neatly lobbed Hughes after latching on to Luke Roberts ball over the top of the defence.
Hughes was replaced by Dafydd Jones between the sticks on 65 minutes and the new custodians first task was to pick Gibbs shot out of the net, the ex-Tranmere Rovers prospect rounding off a mazy run with a superb individual goal.
Towns Walker was then red-carded for violent conduct, but the visitors kept trying to grab a consolation, Heald performing marvels to keep out a header from Craig Wilkinson.
Recent signing Jon Peris-Jones marked his seasons debut for the Harbourmen with goal number six late on – a strike from 15 yards.
Roberts then hit the bar for the hosts before Heald ensured a clean sheet by foiling Tom Sharples.