Remi Garde's men head into the last-16 clash on a high having won in dramatic style at the weekend, though they face a tough test against Shakhtar Donetsk' conquerors
Remi Garde's men made a poor start to the season, with a failure to qualify from the Champions League's play-off stage compounded by shocking Ligue 1 form.
After winning their opening two league fixtures, Lyon then won just one of their next nine to heap the pressure on Garde.
But they have rebounded strongly, with Alexandre Lacazette crucial in his side's form revival as the young striker has contributed 18 goals in all competitions this term.
Lyon climbed to fifth in Ligue 1 on Sunday after a remarkable 2-1 win at Bordeaux that saw them saw score twice in second-half stoppage time.
An experiment to play three at the back went wrong and Bordeaux should have led by more than one goal at the break. Garde re-shuffled his pack though and left delighted after Henri Bedimo and Corentin Tolisso struck in the dying stages.
Unbeaten in all eight of their Europa League matches this season, Lyon finished on top of Group I before edging Chornomorets 1-0 on aggregate in the competition's last 32.
Plzen, meanwhile, dropped into the Europa League after winning just three points in six Group D Champions League fixtures.
But after negotiating their way past 2009 winners Shakhtar Donetsk 3-2 on aggregate in the last 32, they will be hopeful.
Plzen lost for the first time since November on Sunday, though, as their Czech top-flight title hopes took a blow. Sparta Prague beat them 1-0 in the capital to extend their lead at the top of the league to eight points.
Plzen made the last 16 of the Europa League last season, only to be knocked out by Fenerbahce, but are unbeaten in their last five away games in the competition.