United hold big advantage after the first leg
Zlatan Ibrahimovic's hat-trick in the first leg means that United only need to avoid a disaster at the Stade Geoffroy-Guichard to prevail through to the round of 16.
The reason for the game taking place on a Wednesday rather than the Thursday is due to the fact that Olympique Lyonnais, Saint-Etienne's fiercest rivals, play their home leg of their round of 32 tie against AZ Alkmaar, so both can't play on the same night due to safety concerns.
Preparations for the game couldn't have gone much better for Jose Mourinho's men as they come into the game on the back of a tough 2-1 victory away to Blackburn Rovers in the FA Cup on Sunday.
Hosts looking to bounce back after two successive defeats
On the other hand, Les Verts come into the game after falling to a 2-1 defeat to Montpellier on Sunday which has seen them fall four points off a top four place in the Ligue 1 table.
The French side though showed in the first leg that they are a team that shouldn't be underestimated, as if they had took their chances on the night, then the tie would be much more in the balance than it actually is.
Pogba brothers square off once again
The game also sees the reunion once again of the Pogba brothers after both Paul Pogba and Florentin Pogba played in the first leg as well. Therefore the spotlight is likely to be on both as they look to help their side advance to the next round.
In terms of team news for the game, the hosts will be without three attacking players for the game. Alexander Soderlund, Oussama Tannane and Robert Beric are all missing for the game due to injury.
Therefore, Christophe Galtier is likely to pick a similar lineup to one that he chose last week at Old Trafford and he knows that his team has to start well to have any chance of pulling back a huge deficit from the first leg.
Mourinho has confirmed that David de Gea and Antonio Valencia were rested during United's FA Cup win over Blackburn and are expected to come straight back into the team for this game.
Wayne Rooney and Luke Shaw returned to training this week but both have not travelled with the squad for the game while Phil Jones is out of the game due to injury. Ander Herrera will also miss the game due to suspension after picking up his third yellow card of the competition in the first leg.
Saint-Etienne: (4-4-2) Ruffier; Malcuit, Théophile-Catherine, Perrin, Pogba; Jorginho, Veretout, Pajot, Saivet; Hamouma, Monnet-Paquet.
Manchester United: (4-2-3-1) De Gea; Valencia, Smalling, Bailly, Blind; Fellaini, Pogba; Mata, Mkhitaryan, Martial; Ibrahimovic.
Referee: Deniz Aytekin (GER).