The Blues sit bottom of the group with one point, six points behind the leaders Atalanta and four behind Lyon.
David Unsworth’s side, who are still searching for their first win in any competition since the end of September, will be without Leighton Baines, Phil Jagielka, Michael Keane and Wayne Rooney for the crucial game at the Groupama Stadium.
Keane remains sidelined with a leg injury that has needed surgery to remove an infection whilst the three veterans are being rested.
Les Gones are unbeaten in six European home games and a victory could see them leapfrog Atalanta and move into the driving seat with the group stages quickly coming to a close.
Everton haven’t lost successive games in Europe since they lost to Benfica twice in the Europa League during October and November of 2009 but like many records this season, the Blues may just be about to break another - but this one, like those before it, is far from positive.
In Focus: Showing fight
The reverse fixture at Goodison Park a little over two weeks ago was overshadowed by the fracas between Ashley Williams, the entire Lyon team and the first few rows of the Gwladys Street.
Everton have since banned the fan involved with throwing a punch in the direction of goalkeeper Anthony Lopes.
The Blues have also sacked Ronald Koeman and installed David Unsworth as boss on a temporary basis.
If he’s going to be in the job much longer is undecided but Thursday’s result will likely give an indication on the manager’s position.
The French visitors ran out 2-1 winners but for a period, seemed rattled by a noisy Goodison Park crowd and an Everton team that, for a brief moment, played with aggression and passion - the hallmarks of Everton teams of the past.
That ‘Everton’ style has returned, briefly, under Unsworth but the Blues still remain toothless in attack and the soft underbelly of a disjointed defence is a huge weakness.
Unsworth’s audition for the ‘big job’ is yet to go successfully at all and a defeat on Thursday night, despite the Blues uphill battle to get out of the group, may signal the final nail in the coffin on his chances to move up from interim boss to permanent.
He has issues to address, eight o’clock on Thursday night wouldn’t be the worse time to figure some of them out.
A look at: Lyon
Since their victory over Everton in the last group game, Bruno Génésio’s side have gone on to beat Troyes 5-0 and Metz 2-0 in the French Ligue 1.
Former Manchester United midfielder and one time Everton transfer target, Memphis Depay scored a hat-trick in the win over Troyes, taking his tally for the season to six. However, he has only notched one goal in the Europa League - Lyon’s only goal in the 1-1 draw with Apollon Limassol.
Nabil Fekir, who scored from the penalty spot at Goodison Park, scored both goals in the victory against the lowly Metz. Those wins have since pushed Lyon up to 3rd in the table with 22 points. They sit behind only PSG and AS Monaco.
They’ll be without midfielder Clement Grenier as he remains sidelined with a foot injury.
Lyon: Lopes, Tete, Morel, Marcelo, Marcal, Tousart, NDombele, Fekir, Depay, Traore and Diaz.
Everton: Pickford, Kenny, Williams, Holgate, Martina, Davies, Baningime, Sigurdsson, Lennon, Mirallas and Calvert-Lewin.