Goals from Lewis McGugan, Atdhe Nuhiu and Stevie May left the Lions rooted in the bottom three and increased the pressure on manager Holloway.
Millwall have not won a home game since October, a run stretching back 11 matches, and are still three points from safety.
Yet they had plenty of chances to take the lead with Gary Taylor-Fletcher and Aiden O’Brien denied by goal-line clearances, the latter just moments before McGugan’s opener.
But they promptly capitulated with Nuhiu and May wrapping up Wednesday’s first win in eight games before Diego Fabbrini hit a late consolation.
Millwall should have gone ahead after a quarter of an hour when Fabbrini lost his boot but still managed to thread the ball to Lee Gregory in the Wednesday box.
Chris Kirkland, making his first league start of the season in place of the suspended Kieran Westwood, blocked Gregory’s effort but the loose ball fell to Taylor-Fletcher.
The experienced striker was off balance as he prodded the ball forward but it still looked destined for the net until Liam Palmer stuck out a leg and hooked it off the line.
Moments later half The Den thought Taylor-Fletcher had opened the scoring, but his clever backheel at the near post had in fact nestled into the side-netting.
The game’s pivotal moment arrived in the 52nd minute when Gregory chipped the ball across goal towards substitute O’Brien.
The young winger looked certain to score as he threw his head towards the ball, only this time Tom Lees was on hand to make another vital clearance from underneath the crossbar.
Kirkland denied Taylor-Fletcher from the rebound and Wednesday immediately broke to the other end where McGugan coolly slotted home from 15 yards.
The goal knocked the stuffing out of Millwall and they were carved wide open when Nuhiu tapped in the second after a fine run and cross from Jacques Maghoma.
And Maghoma also set up the third for substitute May, who slid the ball through the legs of Lions keeper David Forde to spark chants of ‘sacked in the morning’ towards Holloway from both sets of fans.
Fabbrini pulled one back in stoppage-time but it did little to improve the mood at The Den with Millwall, and Holloway, looking in deep trouble.