However, since United's tragedy in the Champions League they seem to have taken their game to the next level. They have beaten Liverpool 3-2 in the FA Cup and most recently they turned over Manchester City 2-0 in the Premier League.
As for AC Milan, they topped their group with 13 points and in their round of 32 tie they won on away goals after their aggregate score finished 3-3. They drew their first leg 2-2 away at Crvena zvezda, and then 1-1 at the San Siro.
For United, Marcus Rashford suffered an ankle injury during the Manchester derby, there will be an update from Ole Gunnar Solskjær on the extent of the forwards problem when he is on media duties on Wednesday afternoon, around 13:30 GMT.
Paul Pogba, Donny van de Beek and Edinson Cavani all missed Sundays win and will most likely miss Thursday's clash with Milan. Luke Shaw and Anthony Martial both passed late fitness tests to play in that City game so they should still be fit.
Juan Mata and Phil Jones also remain on the injury list. Dean Henderson is set to play after David De Gea has missed the last two Premier League games. Henderson also played in both the games against Real Sociedad. Impressively, the Englishman kept clean sheets in all four games.
Milan manager, Stefano Pioli, has a received a positive update on former red, Zlatan Ibrahimovic, but there are conflicting reports on his availability. The most recent update states that the 39-year-old will miss the first leg at Old Trafford but he will be back for the second game.
Sandro Tonali was rested by Pioli in Milan's 2-0 win over Hellas Verona as a precaution and therefore he should feature against The Red Devils.
There are doubts over Theo Hernandez, Daniel Maldini, Hakan Calhanoglu, Ismael Bennacer, Ante Rebic and Mario Mandzukic, but Diogo Dalot, who is on loan with the Rossoneri from United, is eligible to play.
Manchester United: Henderson; Wan-Bissaka, Bailly, Maguire, Shaw; Fred, McTominay; Greenwood, Fernandes, James; Martial
AC Milan: Donnarumma; Calabria, Kjaer, Romagnoli, Dalot; Tonali, Kessie; Saelemaekers, Diaz, Castillejo; Leao
Ones to watch
Luke Shaw is one of United's most in-form players at the moment. After having his injury setbacks whilst at the club the English left-back has found some consistency. One of his best performance's came in United's last game, when he scored The Red Devils second goal against City. The goal topped off a fantastic game for the 25-year-old where he also picked up the Man of the Match award.
The only player who beats Shaw on form is United's star man, Bruno Fernandes. In that City game the midfielder opened the scoring for United from the penalty spot. After being criticised for not 'turning up' in the big games, Fernandes silenced those who doubted him on Sunday at the Etihad.
The Portugal international has scored 16 and assisted 10 in just 28 games in the Premier League this season, he's now only one goal behind Mohamed Salah in the race for the Golden Boot.
Milan goalkeeper Gianluigi Donnarumma has featured 250 times for his club and country at a senior level, despite only turning 22 recently.
The vice-captain made his debut for the Italian side at just 16, becoming the second-youngest keeper in Italian top-flight history and has been a starter in the side ever since.
Club captain Alessio Romagnoli, who has been compared to Alessandro Nesta, is also a massive player for Milan, his leadership and organisation at the back could cause United problems when they look to attack.
Going forward, Ibrahimovic - if he plays – is the obvious dangerman as United know. The Swede's fellow striker, Rebic is a also a threat after helping Croatia to the World Cup final in 2018, he's also scored 17 in 53 games for the Serie A side.
Head to head
United and Milan's last UEFA encounter came in the Champions League in 2010.
The Italian side won the first four meetings between the two sides, however United were victorious in the last game as they convincingly won 4-0. On that day Wayne Rooney scored twice with Darren Fletcher and Park Ji-sung scoring as well.
The Red's have won four of their previous five games against Milan in Manchester, losing the other one.
Both clubs sit second in their leagues (Serie A and Premier League). With this in mind, this tee's up one of the most mouth-watering encounters in the round of 16.
How to watch and kick off time
The match kicks off at 17:55 (BST) and it will be broadcasted live in the UK on BT Sport.