Lyon, who drew at Ghent in their opening match, are bottom of Group H after Sofiane Feghouli gave Valencia, who are second on three points, a victory against the run of play.
Zenit St Petersburg lead the group with a maximum six points after beating Ghent, who are third with one point, 2-1 at home.
Feghouli scored the only goal with an 18-metre missile that went in under the crossbar at the end of a swift counter-attack three minutes before halftime,
Lyon had a huge chance to level just before the break but Alexandre Lacazette's deflected shot crashed onto the bar.
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The hosts piled on the pressure after the interval but were too clumsy as Valencia continued to be dangerous on the break and their defence held firm.
Valencia goalkeeper Jaume Domenech made a couple of stunning saves in added time to frustrate Lyon, who dominated possession but lacked sharpness.
Lyon next face Zenit in St Petersburg and Valencia host Ghent on Oct. 20.
(Reporting by Julien Pretot; Editing by Rex Gowar)
