The Frenchman injured his ankle in Sunday’s defeat at Brentford and it is feared he will miss the rest of the season.
Moyes, however, spoke of a certain Issa Diop, the most likely candidate to replace Zouma in the starting line-up.
Elsewhere, few changes are expected with Pablo Fornals, Jarrod Bowen and Manuel Lanzini likely to form the forward line behind striker Michail Antonio.
Alphonse Areola, meanwhile, will most likely continue as West Ham’s starting goalkeeper in cup competition and his big-game experience could well be crucial.
Ben Johnson is the favorite to replace Aaron Cresswell, suspended following his red card in the first leg.
With West Ham’s Premier League form ending, Thursday’s visit to Lyon is Moyes’ decisive game of the season. Win and he would have made history.
Predicted West Ham XI: areola; Coufal, Dawson, Diop, Johnson; Rice; Bowen, Soucek, Lanzini; Forms; Antonio.
injured: Zouma (ankle), Ogbonna (knee)
date and time: Thursday, April 14, 2022, 8:00 p.m. BST
Place: Groupama Stadium