Ole Gunnar Solskjaer’s side will seek to avenge last season’s Europa League final defeat to the Spanish club and pick up their first points in Group F after a 2-1 reverse to Swiss side Young Boys on matchday one.
Manchester United will still be smarting from a 2-1 defeat in Berne and have also failed to score in their last two home games.
They were dumped out of the League Cup by West Ham and lost by the same 1-0 scoreline to Aston Villa in the Premier League on Saturday, with Bruno Fernandes missing an injury-time penalty.
Solskjaer’s side are winless in their last seven games against Spanish teams in the Champions League (D3 L4), with their last such victory coming against Real Sociedad back in October 2013.
They will bid to avenge their Europa League final defeat, when downed 11-10 on penalties, and are 1.53 to win the clash.
United suffered defeat against Young Boys on matchday one, but they have never lost their opening two matches of a major European campaign in their history.
Villarreal twice came from behind to secure a Champions League point against Atalanta on matchday one, and they are also unbeaten domestically after six games in La Liga, winning one and drawing five, including their last three.
Unai Emery’s side are unbeaten in their last 16 major European games (W12 D4) across the Europa League and Champions League, the longest current run of any side.
They are 6.5 to win at Old Trafford, while the draw is on offer at 4.33.
The five meetings in European competition between the two sides have all ended in draws, with four of them goalless except for last season’s Europa League final (1-1).
The four Champions League clashes between Manchester United and Villarreal have all finished 0-0, making it the most played fixture in the history of the competition to see no goals scored.
It is 15.00 that the game ends in a goalless draw, while it is 5.2 that the game ends in a scoring draw.