Oleg Shatov put the hosts in front with a composed finish after 15 minutes, while Artem Dzyuba sealed the points in the 74th to ensure Zenit, who had already qualified for the last 16, will finish top of a Champions League group for the first time.
Valencia's evening turned from bad to worse with 10 minutes left as they were reduced to 10 men when Ruben Vezo was sent off for bringing down Shatov who was clean through on goal.
The Russians have 15 points ahead of second-placed Valencia with six also from five games. Zenit's final group opponents Ghent are third with four points ahead of their match later on Tuesday at Olympique Lyonnais, who are bottom with one point.
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Andre Villas-Boas' Zenit side almost went in front after 13 minutes when Domenico Criscito's left wing cross was deflected goalwards but Valencia defender Aymen Abdennour cleared the ball off the line but the home side took the lead two minutes later.
Valencia were unable to clear the ball and Dzyuba slipped a pass through to Russian international Shatov who showed great composure to chip onrushing goalkeeper Jaume Domenech to put Zenit in front.
The home side were dominant after the break, with Criscito going close, although the visitors thought they had grabbed an equaliser midway through the second half.
The ball was slipped through to substitute Santi Mina who produced a fine right-foot finish past Yuri Lodygin but had strayed into an offside position.
Zenit doubled their lead when captain Danny played a neat one-two with Shatov and, though the Portuguese international was clear on goal, he laid the ball off to Dzyuba who slotted into an empty net for his fifth goal in this season's competition.
(Writing by Dmitriy Rogovitskiy in Moscow; Editing by Ken Ferris)
