Mainz had conceded six times without reply across successive Bundesliga defeats before the international break, and there appeared to be no end to their misery in a bruising first half here.
Leverkusen hit the front early from the penalty spot, with Alejandro Grimaldo coolly converting from 12 yards after Jonas Hofmann was tripped by Nikolas Veratschnig.
Kasper Hjulmand’s men doubled their advantage on 24’ through the in-form Christian Kofane, who rounded off a tremendously intricate spell of one-touch football on the edge of the Mainz box by lashing into the bottom corner to score for a third successive game.
The hosts had failed to score in all three prior home games this term, but did respond here in fortuitous fashion.
Die Werkself made a mess of dealing with a long throw into their box, with Loic Bade’s poor clearance pounced upon and finished by Lee Jae-sung.
Momentum was with Bo Henriksen’s side, but their comeback hopes were doused when Leverkusen turned the ball over high up the pitch and restored their two-goal lead through Grimaldo, who doubled his personal tally by slotting at the near post having been found by Hofmann.
Paul Nebel threatened to get Mainz back into the game with a wayward cross that came back off the bar before the break, but once play resumed, Grimaldo came inches away from completing a hat-trick with a low drive that whistled just wide of the post.
An unlikely route back into the contest fell the 05ers’ way when Arnaud Nordin’s long-range strike came back off the woodwork and Phillipp Mwene was felled by Arthur as he attempted to control the rebound.
Former Leverkusen midfielder Nadiem Amiri stepped up to slot home from 12 yards for the second time in three matches, breathing fresh life into the beleaguered home support.
Martin Terrier came off the bench to make his first Leverkusen appearance since January, and marked it with a goal as he slotted home from inside the six-yard box.
That looked to have put the game to bed, but Mainz refused to lie down as Armindo Sleb picked out the far corner to remarkably make it 4-3 in the 90th minute.
The resurgent hosts ultimately fell just short in their miraculous comeback efforts, with this defeat stretching their winless home run in the Bundesliga to nine matches dating back to February, and leaves them in the bottom three.
Leverkusen, meanwhile, have now won three successive Bundesliga games, with a fifth victory in seven meetings serving as the perfect warm-up for a UEFA Champions League blockbuster against Paris Saint-Germain in midweek.
Flashscore Man of the Match: Alejandro Grimaldo (Bayer Leverkusen)