Guilio Donati opened the scoring on 58 minutes after what proved a forgettable first-half display from both sides.
They were quick to add to their lead, too, as Kyriakos Papadopoulos headed home a second with his first touch of the ball five minutes to help Roger Schmidt's side move one point clear of AS Monaco at the summit.
Below, Sports Mole takes a closer look at events in Leverkusen tonight.
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On target: 8
ZENIT ST PETERSBURG
On target: 1
Was the result fair?
Without a doubt. You need only glance at Zenit's shots total in the above statistics to see that Andre Villas-Boas's side did nowhere near enough to claim anything from this game.
Bayer Leverkusen's performance
Leverkusen boss Roger Schmidt will take a great deal of satisfaction from tonight's win after watching his attack string together some delightful moves, while their defence managed to keep some big names quiet throughout. The spotlight was on their defence after they let a three-goal lead slip against Stuttgart on Saturday, but the manager deserves credit for the way in which they responded to that criticism.
They struggled to get the first goal, but once they opened the scoring it was plain sailing and added another shortly after. They seldom had a sight at goal after that - and did not need to. Despite the disappointment of Saturday, Schmidt's side had the confidence to invite Zenit's attack and comfortably repelled everything that came their way.
Their attacking display might make for one or two concerns as the hosts seemed to lack an outlet, with striker Stefan Kiessling largely uninfluential, but the positives outweighed the negatives for Schmidt and co tonight.
Zenit St Petersburg's performance
The Russian giants came to life far too late to salvage anything tonight and deservedly slumped to their first defeat of the season in all competitions. It was not until Wendell's dismissal with 11 minutes remaining that Zenit began to look dangerous, yet a goal was never coming tonight and it was evident from the start.
They defended well at times, but it was shortcomings at the other end of the field that will make tonight's flight back to Russia a long one for Villas-Boas, whose supposed big names failed him in the final third this evening.
The towering figure of Hulk found himself being man-handled by a left-back half his size in Wendell. Hulk's woes extended to lone striker Salomon Rondon, who was completely isolated as Zenit's spearhead, while Danny did not help his cause with a truly poor performance in the number 10 role.
Sports Mole's man of the match
Lars Bender: The Bayer Leverkusen midfielder was exceptional and a prime factor in his side earning a deserved clean sheet tonight. He broke up attack after attack for the visitors and distributed possession cleverly throughout the night. The Germany international has been dogged by injuries in recent years, but he will have a big say in his side's Champions League journey if he can stay fit.
Had it not been for this moment of stupidity then left-back Wendell would have been the stand-out candidate for man of the match, but his dismissal on 79 minutes marred what was an outstanding overall performance from the Brazilian.
After being booked for leaving his mark on Hulk, Wendell was later guilty of a cynical handball to prevent an attack that he had the pace to deal with legitimately. With 11 minutes remaining, the incident jeopardised his side's chance of victory and he now finds himself suspended for the crucial trip to Russia in a fortnight.
Bjorn Kuipers had a fine game. The no-nonsense Dutchman set his stall out very early by correctly booking no fewer than three players inside the first 17 minutes to establish his authority.
Kuipers handed out a further four yellows - including two for Wendell, whose cynical handball saw him leave the field - and he can rest easy knowing that he did his job well tonight.
Bayer Leverkusen: The Germans resume Bundesliga duties in Saturday's visit of Schalke 04 to the BayArena.
Zenit St Petersburg: Zenit, unbeaten in their first 10 games in the Russian Premier League, look to maintain their impressive domestic form when they host Mordovya on Sunday evening.