Former Wrexham striker Marc Williams netted twice as Llandudno moved back up to second in the Cymru North with a convincing win at the New Stadium on Tuesday evening.
Williams broke the deadlock five minutes before half time with a header to edge his side in front.
Hotspur had a goal disallowed close to the interval.
Home keeper Adam Martin did well to deny Williams a second, but he was powerless to stop Toby Jones making it two on 59 minutes with a cracking strike into the left corner.
Holyhead fought back hard and were unlucky not to halve the deficit from a goalmouth scramble, but a third Tudno goal after 70 minutes, Williams on target, made it more or less game over.
Two minutes from time, Mason Blackwell-Jones finished smartly to make it 4-0 and Hotspur were denied even a consolation when Shaun Pearson saved a late penalty.
On what was otherwise a good day for Hotspur, with news they have secured a new lease arrangement on their ground, their on-the-field worries continued as their run of matches without a victory stretched to 14.
They travel to Penrhyncoch for a crucial clash of the bottom two this Saturday.
Adam Martin
Dafydd Jones (Huw Watkins 89)
Jamie Pick
Alex Jones (c)
Mitchell Jones
Harry Lewis
Chris Jones
Jay Gibbs
Dylan Summers-Jones
Dan Mowbray
Cory Williams
Shaun Pearson (c)
Morgan Owen
Mike Williams (John Bennett 75)
Gareth Evans
Mason Blackwell-Jones
Shaun Cavanagh (Sam Jones 75)
Luke Smith
Julian Williams (Joe Chaplin 67)
Telor Williams
Toby Jones (Danny Brookwell 66)
Marc Williams (Sean McCaffery 75)
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