All looked to be going well for Dusan Uhrin's men when Tomas Horava put them in front after just three minutes in France last week, but that was as good as it got for the Czech champions.
Gueida Fofana levelled the scores nine minutes later, before three goals in 17 second-half minutes from Alexandre Lacazette, Arnold Mvuemba and Fofana with his second put Remi Garde's men out of sight.
Uhrin's side may also find solace in the fact that twice this season Lyon have lost by scorelines that would see Plzen through - 5-1 at Montpellier in October and 4-0 at Paris Saint-Germain in December.
Their last two results in the Czech Liga have seen them fall 10 points behind leaders Sparta Prague - a 1-0 defeat to their title rivals and a goalless draw with Slovacko sandwiching last week's thumping in Lyon.
For the French outfit, Sunday's 3-2 home defeat at the hands of title-chasing Monaco was a first defeat in eight matches in all competitions.
Lyon remain undefeated in this season's Europa League, but Sunday's reverse left them in fifth place in Ligue 1, three points adrift of a Europa League place and eight below Lille, who occupy the third and final UEFA Champions League qualification spot.
