The Bundesliga side have been in poor form but ensured they ended the group stage of the Champions League with a victory over the group winners
With both sides already through to the next stage - and unable to finish any higher or lower - Leverkusen dominated the game, often finding visiting goalkeeper Morgan De Sanctis to be a frustrating obstacle.
Javier Hernandez, without a goal since the start of October, was repeatedly denied, before Vladlen Yurchenko's glorious effort broke the deadlock on the half-hour mark.
Julian Brandt's deflected second arrived after 48 minutes, and, although Leverkusen's momentum then slowed and Corentin Jean hit the post at the other end, De Sanctis was unfortunate to turn Wendell's penalty into his own net with eight minutes remaining.
Monaco, like the hosts, had been yet to lose in Group E, but a below-par performance reflected a team sheet that showed nine changes from their 5-0 demolition of Bastia in Ligue 1 on Saturday.
As the two teams switch their focus to the knockout rounds, Leverkusen can take encouragement from a first victory against the in-form French club.
De Sanctis had to be alert to deny Javier Hernandez high at his near post with the game's first chance.The visiting goalkeeper was rather less impressive when he flapped at Brandt's cross from the right, but Julian Baumgartlinger sliced horribly wide as he spun onto the loose ball.
Although Stefan Kiessling served up two glorious pieces of skill to twice beat Andrea Raggi, his centre was cleared ahead of Hernandez, and the Mexico international shot straight at De Sanctis from his strike partner's next neat lay-off.
Leverkusen remained on the front foot, however, and opened the scoring after 30 minutes.
De Sanctis did brilliantly to deny Hernandez for a third time after Brandt led a counter, but, with the ball not cleared, Yurchenko then unleashed a stunning strike into the top corner from 20 yards.
With Monaco struggling, De Sanctis was back in action to somehow block Aleksandar Dragovic's unmarked header from a corner, before diving at Hernandez's feet.
A second arrived shortly after half-time, though.
Brandt spread the ball wide to Hakan Calhanoglu and then ran onto the return, prodding fortunately into the net via Jemerson's desperate lunge.
Monaco should have pulled one back when Joao Moutinho squared for Jean in front of goal, but the 21-year-old turned his finish against the foot of the post.
But Leverkusen instead extended their lead further as Robbie Kruse tempted a lunge from Abdou Diallo in the area to earn a penalty.
Having seen Hernandez miss a spot-kick in the Bundesliga at the weekend, Wendell stepped up. The Brazilian full-back struck the bar, but the ball bounced down against De Sanctis and across the line to clinch the emphatic win.
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