A late 1-0 victory over Young Boys on matchday five secured United's place in the last 16 of the competition with a game to spare, and there is even the outside chance that they could still win the group.
A win over Valencia coupled with Juventus falling to a shock defeat at the hands of Young Boys would see United leapfrog the Italian giants, although the Red Devils will know that is an unlikely scenario.
Here, Sports Mole looks at how Jose Mourinho could line his side up for the trip to Spain.
United are facing something of an injury crisis at the back, with Victor Lindelof, Luke Shaw and Chris Smalling definitely sidelined for this match and Eric Bailly doubtful due to a muscle problem.
Should Bailly not recover in time then Marcos Rojo is Mourinho's only recognised centre-back to join Phil Jones in the side, although he has also played Scott McTominay in defence on occasions this season.
Mourinho has already hinted at changes, confirming that Paul Pogba will start after spending the last two matches on the bench and also dropping hints that Sergio Romero and Andreas Pereira could feature.
The weekend goalscoring performances of Marcus Rashford, Juan Mata and Romelu Lukaku could be enough for all three to retain their places in the side, though, while Ashley Young - who was also on the scoresheet - is expected to continue on the left due to Shaw's absence.