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.
The only crumb of comfort for Plzen will come in scoring the early away goal, meaning a 3-0 win in the Doosan Arena will see them progress to the last eight of the competition.
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.
The Czech outfit, meanwhile, have won by at least three clear goals on six occasions this season in competitive games in all competitions, albeit not against the quality of opposition they will face on Thursday.
Plzen come into the game in indifferent form, without a win in three matches having won the three immediately before those.
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.
Jimmy Briand scored twice against Monaco, his seventh and eighth goals of the campaign, although the 28-year-old is yet to get off the mark in this competition.
The hosts will be without defender Roman Hubnik after his booking in the first leg ruled him out through suspension.
Lyon midfielder Steed Malbranque missed the defeat at Monaco with an ankle problem and remains doubtful, while Clement Grenier has not featured in any of the past three games after struggling with a groin injury.
