Therefore, Wednesday's encounter could prove to be a tough test for the home side, with anything less than a victory no doubt adding to the unassailable pressure that the United boss is already under.
Let's take a look at everything you need to know ahead of the Champions League clash.
United forward Anthony Martial is unavailable for Wednesday's match as he nears closer to full fitness after picking up a knock during international duty.
And despite captain Harry Maguire coming through the Leicester game unscathed after his recent calf injury, his fellow defender Raphael Varane is absent due to an ongoing groin issue following the UEFA Nations League Final.
The South American pair were still playing for their respective nations during Friday morning, so were therefore unfit to play against The Foxes in United's 4-2 loss on Sunday.
Aaron Wan-Bissaka is available for selection again after his suspension for the red card against Young Boys, which originally gave him a two-game ban, was reduced to just one match after a successful appeal.
As for the visitors, centre-half Rafael Toloi looks set to miss out after he was taken off during the 4-1 victory over Empoli on Sunday.
Manchester United: De gea, Shaw, Maguire, Lindelof, Wan-Bissaka, McTominay, Pogba, Rashford, Fernandes, Sancho, Ronaldo
Atalanta: Musso, Palomino, Demiral, Freuler, Maehle, Koopmeiners, de Roon, Zappacosta, Pasalic, Muriel, Ilicic
One to watch:
Our one to watch for Wednesday's match is United's number seven, Cristiano Ronaldo.
After a lightning quick start on his return to Old Trafford in which the Portuguese scored five goals in his first five appearances, his impact has started to decrease in recent weeks.
Not only has the 36-year-old failed to find the back of the net in his last two outings, but it has been his lack of authority in these games that has been most concerning.
After an illustrious career, it is fair to say that Ronaldo is still an outstanding goalscorer, but the majority of his play comes in and around the box.
United have struggled to create clear cut chances in recent games and in turn, the five-time Ballon d'Or winner has been starved of service.
Yet even in matches when United have been on the back-foot for large periods, such as the game against Villarreal, Ronaldo has found that knack of being in the right place at the right time to score a crucial goal.
It is rare to see the Portuguese go three games without scoring, so even if Ronaldo is a bystander for parts of Wednesday's game, perhaps we should expect to see him pop up with a vital goal.
Head to head:
The two sides have never faced each other in the clubs' histories, so it is hard to predict how both teams will approach the game.
However, Atalanta sit top of the group with four points whilst United sit third with three points.
This is a must-win game for the home side if they have high hopes of topping the group, whilst Atalanta will be confident that they can come to Old Trafford and get a result.
How to watch:
The 20:00 BST game will be broadcast live on BT Sport 2 from 19:00 BST or on the BT Sport app.