Millwall had not lost in 14 home games but Chris Westwood and Kevin Betsy popped up after the break to seal Gary Waddock's first win since taking charge and give the Chairboys their first victory in 14 attempts.
The home side had the best of the first half, but the first chance fell to Wycombe after 16 minutes when Westwood headed Scott Davies' cross over.
Two minutes later Lions skipper Paul Robinson should have opened the scoring but headed wide.
Millwall roared out of the blocks after the break only to be dealt a sucker punch after 56 minutes when Westwood rose highest to head home John Mousinho's corner.
And with the Lions pressing for an equaliser, Wycombe sealed the points 18 minutes from time when Davies slipped Betsy through and the midfielder ran 40 yards before slotting home.