Benitez hopes to have close-season signing Alberto Aquilani available but his midfield will be without captain Steven Gerrard (groin) and Albert Riera (hamstring) while defenders Martin Kelly (ankle) and Martin Skrtel (muscle) are also out.
Liverpool have lost six of their last seven matches in all competitions, including the 2-1 home defeat by Lyon two weeks ago, and their hopes of reaching the knockout stage will be hanging by a thread if they lose at Stade Gerland.
Lyon top Group E with nine points from their three matches and will qualify for the last 16 if they win.
Fiorentina, who host bottom side Debrecen, are second with six points, followed by Liverpool (3), and the Hungarians (0).
Liverpool, who have won the European Cup five times and have reached at least the quarter-finals for the last three seasons, have shown nothing like that kind of form this term, having lost eight of their 16 games in all competitions.
Their Spain striker Fernando Torres, replaced after 63 minutes despite scoring in Saturday's 3-1 Premier League defeat at Fulham is likely to play in pain with an adductor muscle injury suffered on international duty last month.
"We are trying to manage (him) because he was close to having an operation. We have to take Fernando to Lyon because we don't have too many options," Benitez was quoted as saying on the club website (www.liverpoolfc.tv) on Monday.
Glen Johnson (calf), Daniel Agger (back), David Ngog (ankle) and Fabio Aurelio (calf) are among those fighting to be fit.
Jamie Carragher, sent off at Fulham along with Philipp Degen, said afterwards: "These are tough times, and it hurts.
"We made up for a few things last week by beating Manchester United, but we have had two defeats since.
"We have got to sort this out this week on the training pitch because Lyon is another massive game."
Lyon bounced back from two league defeats by winning 1-0 at arch-rivals St Etienne on Saturday and are second in the French title race, two points behind Girondins Bordeaux.
Bafetimbi Gomis came on to score the winner against his former club six minutes from time, and showed that the French side, unlike Liverpool, can rely on their substitutes if needed.
France keeper Hugo Lloris produced an outstanding display, denying St Etienne several times with spectacular saves.
"Even if we were under pressure, once again, we finished very strongly, just like at Anfield," said club president Jean-Michel Aulas.
"Now we are thinking of Liverpool, it is going to be a very tough match."
Argentine striker Lisandro Lopez is expected to start up front, backed by France forward Sidney Govou and Brazilian Michel Bastos on the wings.
France midfielder Jeremy Toulalan is expected to extend his spell in central defence because Jean-Alain Boumsong is still sidelined with a groin injury.
Lyon: 1-Hugo Lloris; 2-Francois Clerc, 3-Cris, 28-Jeremy Toulalan, 20-Aly Cissokho; 17-Jean Makoun, 8-Miralem Pjanic, 10-Ederson; 14-Sidney Govou, 7-Michel Bastos; 9-Lisandro Lopez
Liverpool: 25-Pepe Reina; 2-Glen Johnson, 23-Jamie Carragher, 27-Philipp Degen, 16-Sotirios Kyrgiakos; 22-Emiliano Insua, 20-Javier Mascherano, 4-Alberto Aquilani, 18-Dirk Kuyt; 15-Yossi Benayoun, 9-Fernando Torres
Referee: Frank de Bleeckere (Belgium).
(Additional reporting and writing by Julien Pretot in Paris, Editing by Ken Ferris)