The 32-year-old was stretchered off with a calf injury in a recent pre-season clash with Levante and was not involved in his side's weekend draw with Leeds United, so Manu Trigueros and new arrival Manu Morlanes ought to line up in the middle.
With the coronavirus pandemic still raging, Etienne Capoue, Francis Coquelin and Vicente Iborra have all fallen victim to a recent outbreak, leaving Unai Emery extremely short of options in the engine room.
Juan Foyth - who has just signed permanently from Tottenham Hotspur - and the veteran Raul Albiol could form the last line of defence, with Pau Torres only just returning from Olympic duty with Spain.
The Yellow Submarine have no such concerns in the full-back areas - where Mario Gaspar and Alfonso Pedraza will hope to get the nods - while Yeremy and Boulaye Dia could feature further up the field on the flanks as Samuel Chukwueze recovers from his hip injury.
Gerard Moreno's seven Europa League goals set Villarreal on their way to continental glory last term, and the Spain international could find himself alongside Paco Alcacer - now back in the fold - up top.
Villarreal possible starting lineup: Asenjo; Gaspar, Foyth, Albiol, Pedraza; Yeremy, Morlanes, Trigueros, Dia; Moreno, Alcacer