Maxwell Cornet put Lyon in front eight minutes before the break and Alexandre Lacazette sealed all three points for the French side in the 76th minute with a solo breakaway effort.
Gent’s 2-1 win over Group H leaders Zenit St Petersburg meant even a win would not have been enough for Valencia to advance to the last 16.
Neville and his team will drop into the Europa League, where they will join the Englishman’s former club Manchester United.
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Neville, who replaced Nuno Espirito Santo as coach at the Mestalla, spent much of the game on the edge of his technical area, following the game intently and issuing instructions via hand signals.
Valencia twice threatened from set-pieces when Shkodran Mustafi steered Rodrigo de Paul’s corner on to Anthony Lopes’s right post before the German hit the back of the net, only for the effort to be ruled out for an infringement in the build-up.
Valencia goalkeeper Jaume Domenech denied Cornet and Corentin Tolisso while Lopes had to be alert to keep out Paco Alcacer’s header following fine work by Dani Parejo and Jose Gaya.
Cornet gave Lyon the lead after forcing Gaya on to his heels before firing a curling left-foot strike that looped into the top corner having taken the slightest of deflections.
With Valencia pushing for the equaliser there was always the risk of a counter-attack and, with 14 minutes remaining, Lacazette held off Aymen Abdennour before sliding the ball beyond Domenech.
(Reporting by Michael Church, Editing by Ed Osmond)
