Having progressed in one knockout competitions with victory at Shrewsbury on Monday, the Reds will be strong favourites to do so again but will be made to work hard by Jess Thorup's outfit.
Their tactical and technical game plan stifled United's attack in Jutland, and they will sit deep and defend in numbers as they look to protect their slender first match advantage and quieten the Old Trafford faithful.
The Reds are looking to overturn a 1-2 first leg deficit in a bid for a place in the last 16, and the Dutchman said:
"For our opponents, it shall be very exciting for them to play in Old Trafford, it is the match of their lives and Manchester United need to play with desire, hunger and at a good rhythm.
"I know that everyone is thinking we have to win against this opponent but they are a good squad and we have seen that they have quality.
"We have to beat them, they have very good defensive organisation and they are doing that with diagonal pressing so I want us to do that also.
"We have to score that is for certain, they shall 'park the bus' I think so we have to disorganise them and be creative."
David De Gea will miss out so Sergio Romero will again deputise, but Marcos Rojo is in the squad and could feature after a two month lay-off.
Matteo Darmian and Antonio Valencia are back in training but neither will be included as the match against the Danes will come too soon.
Phil Jones, Ashley Young, Bastian Schweinsteiger, Wayne Rooney and Marouane Fellaini are all out and Adnan Januzaj is cup tied.
Chris Smalling did not train with the group on Wednesday so his participation remains unclear.
Many would have expected this second leg to be all but a dead rubber but instead Midtjylland arrive in MI6 looking to avoid defeat and chasing the biggest shock in the competition's history in what will be the defining moment of many of their squad's careers.
Currently third in the Superliga table, the first leg win over United was their first competitive outing of 2016 as they resume domestic duties on Monday after the winter break.
Form guide: United W W D L L W Midtjylland D L L W W W
Match odds: 4/1 Draw 11-2 Midtjylland 15/1
Referee: Istvan Vad (Hungary) will take charge of United for the first time
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