The Reds warmed up for the fixture with a convincing 2-0 win against Watford on Saturday as goals from Juan Mata and Anthony Martial either side of half-time helped United maintain their push for a top-four finish.
It's been 40 years since these two European giants have met in a fixture, but it will be the first time that St Etienne have ever played at Old Trafford.
Ahead of the first leg at the Theatre of Dreams, here's everything you need to know about United's opposition.
Full Name: Association Sportive de Saint-Étienne Loire
Nickname(s): Les Verts (The Greens), ASSE
Founded: 1919; 98 years ago
Ground & Capacity: Stade Geoffroy-Guichard; 42,000.
The season so far...
The French outfit are sitting in fifth place in Ligue 1, one point off fourth-placed Olympique Lyonnais - their main rivals. ASSE secured a 4-0 win over Lorient on Sunday to continue their form in France, and have lost just once in their previous six league games.
The man on the touchline
Christophe Galtier has been at ASSE since 2009 and has guided the club to the Europa League group stages in the previous four seasons. As well as this achievement, the 50-year-old lead Saint-Etienne to success in the 2012/13 Coupe de Ligue when they were 1-0 winners over Rennes.
As well as a managerial career with the 10 time Ligue 1 winners, Galtier has also had spells with Marseille and Aris Thessaloniki. The one-time defender spent the majority of his playing career in France playing for the likes of Lille, Marseille and Toulouse.
Loic Perrin can only be described as a 'leader of men' in the St Etienne dressing room. The 31-year-old veteran is currently in his 14th season with Les Verts and is close to knocking up his 350th appearance for the club.
Pogba v Pogba
One of the key stories building up to this eagerly anticipating fixture is the meeting between Paul Pogba, and his brother Florentin, who plays for ASSE. This will be the first time that the pair will come up against each other in their professional careers. The world's most expensive player has only just returned to United, and is relishing the chance to come up against his older brother.
Florentin has been with Saint-Etienne since 2012, and likely to deal with his younger brother on Thursday during any set-pieces that may take place. The pair have another brother, Mathias (the twin of Florentin), who plays his football with Eredivisie club Sparta Rotterdam.
Speaking ahead of the fixture, Florentin said: "I watched the draw and, when I saw who we got, my first reaction was: 'Yes, that's a dream that's going to be fulfilled'," Florentin told The Observer. "They will all be in the stadium watching, including Mathias, I think.
We used to play every day and hope that one day all three of us would play together in a professional match. That was the biggest dream. We haven't managed it yet but having two of us together on the pitch is already good." He added.
The One to Watch
Arguably one of the star players to watch is Romain Hamouma. The 29-year-old has scored six times in 25 league appearances this season, as well as creating over 30 chances. The number 21 has been at the club since 2012, and is a regular starter under Galtier. Hamouma is a very versatile player and is usually used as a winger, attacking midfielder or a lone striker.
The Reds have failed to tie down a regular left-back this season with the likes of Matteo Darmian, Luke Shaw, Marcos Rojo and Daley Blind all featuring in the full-back position. Hamouma has been a strong threat this season for ASSE and if Galtier sets him up on the right-side of midfield, the chosen left-back will have to be prepared for a difficult encounter.