In their first Group F match, the Red Devils were defeated 2-1 by Young Boys, while the Yellow Submarine were held to a 2-2 draw at home by Atalanta.
When put under duress Ole Gunnar Solskjaer appears to be missing three of his regular back four on Wednesday night.
Aaron Wan-Bissaka is suspended after receiving a straight red card in the Champions League last time out, while Luke Shaw and Harry Maguire are both out with injuries.
Donny van de Beek, Jadon Sancho, Jesse Lingard, Anthony Martial, and Edinson Cavani will all be in contention to start against Villarreal.
Cristiano Ronaldo has 13 goals in 19 career games against Villarreal, but only two of them have come in the last six.
Gerard Moreno, who scored in Villarreal’s Europa League final victory over Manchester United in May, appears to be unavailable after missing the weekend match against Real Madrid.
Meanwhile, the away team is still without highly rated winger Samuel Chukwueze. Dani Raba and Yeremi Pino have also been ruled out. Francis Coquelin has been placed on leave.
Pau Torres returned from a long break earlier this month and will face Manchester United in this match.
Manchester United have lost three of their last four games in all competitions, and manager Ole Gunnar Solskjaer is under pressure after a busy summer transfer window. After losing their first Champions League game away to Young Boys, the Red Devils are already on the back foot in the competition. They lost on penalties to Villarreal in the Europa League final last season and have drawn all five meetings within 90 minutes.
Villarreal have struggled since winning the Europa League final in May, drawing six of their first seven matches this season in all competitions. Given these two clubs’ head-to-head record, another draw on Wednesday appears highly likely.
The pressure is mounting on Solskjaer as Manchester United fans expect their team to perform at a much higher level, particularly in games they are expected to win.
Wednesday’s game is another that the Red Devils will be favorites to win, and a defeat here would severely jeopardize their chances of qualifying for the Champions League.
Solskjaer is desperate for a response from his players, but they could be in for another difficult evening against a resilient Villarreal team that has been difficult to break down so far this season. Another draw between the two sides at Old Trafford could be on the cards.
Manchester United possible starting lineup:
De Gea; Dalot, Lindelof, Varane, Telles; McTominay, Fred; Greenwood, Fernandes, Pogba; Ronaldo
Villarreal possible starting lineup:
Rulli; Foyth, Albiol, Torres, A. Moreno; Parejo, Capoue, Trigueros; Danjuma, Alcacer, Pino
Our Prediction: Manchester United 1-1 Villarreal