With the likes of Wayne Rooney, Juan Mata, Chris Smalling and even David De Gea injured and likely to miss Thursday's clash with Anderlecht, a gaggle of unlikely lads will look to propel the three-time European champions to a first ever victory in the continent's secondary club competition.
The much-maligned and oft-derided Marouane Fellaini captained United to a 3-0 win away to Sunderland on Sunday and unless Michael Carrick is restored to Thursday's starting line-up, the Belgian could find himself wearing the armband again against the club where he began his youth career.
Until a week ago, England full-back Luke Shaw appeared to have no future at United but after making a rare start against the Black Cats – he was taken off after an hour as a precaution – manager Jose Mourinho suggested afterwards that the 21-year would start on Thursday as well.
And with De Gea nursing a hip complaint, Sergio Romero looks set to deputise in goal once again.
United may be hamstrung by injures but it might be something of a blessing in disguise now that Zlatan Ibrahimovic is back from suspension and Paul Pogba recovered from injury as it gives Mourinho the chance to pick a settled outfit.
Shaw may not start, though, with Antonio Valencia fit again and ready to resume right-back duties, which may see Matteo Darmian switch to the opposite flank.
But the England left-back could play a pivotal role in United's destiny this season – something which seemed unimaginable 10 days ago when Mourinho blasted him over his commitment and dedication.
The Europa League has become United and Mourinho's number one priority this season as winning it would guarantee Champions League football next season.
'We can win'
Too many draws, particularly at home against modest opponents, has been the bane of United's season that has left them four points behind rivals Manchester City in fourth – the final Champions League qualification spot.
Worse than that, Mourinho's former employers Chelsea are 18 points ahead and on the brink of romping to a second title in three years.
"We want to fight in the Premier League until it's mathematically impossible but the Premier League, we cannot win it, and the Europa League we can," admitted Mourinho after the Sunderland match.
"We have eight teams in the competition and we are in the quarter-finals – it's a competition we can win. Honestly we think about it."
Having already won the League Cup, lifting a European trophy as well would go some way to salvaging United's season, and rectifying an historic anomaly.
United's record in Europe's secondary competition is abysmal, with the likes of Torpedo Moscow and Rotor Volgograd knocking them out in the early stages during rare forays into the competition over the years.
Their best result was back in the precursor to the old UEFA Cup, the Inter-Cities Fairs Cup, where United reached the semi-finals in 1964/65, only to lose to Hungary's Ferencvaros, then a much tougher prospect than today.
Another Hungarian side, Videoton, ended their UEFA Cup interest 20 years later at the quarter-final stage and since then United's best Europa League efforts have seen them lose at the last 16 stage in 2011/12 to Atletic Bilbao and last season against Liverpool.
But there are good omens associated with Thursday's opponents Anderlecht.
They were United's first ever European opponents in the 1956/57 European Cup and following a 2-0 win in Brussels, the Red Devils recorded what remains their record European victory – a 10-0 thumping played at City's Maine Road as Old Trafford didn't have any floodlights.
Come Thursday, United, Mourinho and his motley crew will be hoping that the Brussels outfit can once again be the victims of a glorious episode in the Old Trafford outfit's history.