The Danes lost 4-1 in Portugal in the first leg last week, so have it all to do if they are to remain in Europe's elite competition.
Match preview
Indeed, Rasmus Ankersen's side were second best throughout the 90 minutes at Estadio da Luz last Tuesday, with their only shot on target across the game being Pione Sisto's converted penalty in the 77th minute.
Had the Danish winger failed to tuck the ball away from 12 yards, there is little doubt that Midtjylland would effectively have been dumped out of the competition after Goncalo Ramos had completed his hat-trick after the break to add to his side's three unanswered first-half strikes.
Midtjylland finished second for the second successive season in the Danish Superliga last time around, but they did manage to lift the Danish Cup for only the second time in their history having missed out on the Europa League knockout stage by a point.
The Wolves have only once made it to the Champions League group stage, when they finished bottom with only two points in the 2020-21 season, and that tally looks unlikely to be added to this campaign unless they can pull off a remarkable result against Benfica on Tuesday.
Benfica, of course, reached the last eight of the Champions League for the first time in six years last season, when they ran eventual runners-up Liverpool very close over two legs.
Domestically, though, there was major disappointment, with a third-placed finish in the Portuguese Primeira Liga coming alongside a runners-up medal in the League Cup and a fifth-round exit in the Taca de Portugal.
With top goalscorer Darwin Nunez departing for Liverpool in a move which could rise to £80m, it remains to be seen whether Roger Schmidt's side can push champions Porto closer in the German boss's first season in charge of the club.
On the evidence of last week's first leg, Ramos looks set to fill the goalscoring void of the Uruguayan, with Schmidt likely to be keen for his side to avoid any complacency in Denmark given their heavy lead.
FC Midtjylland Champions League form:
FC Midtjylland form (all competitions):
Benfica Champions League form:
Benfica form (all competitions):
Team News
Midtjylland will be without Evander, with the midfielder likely to return from a torn muscle towards the end of August.
Raphael Onyedika returned to the starting XI in the weekend's 3-3 draw at Lyngby, with the 21-year-old likely to start again in order to provide more midfield steel.
Benfica, meanwhile, will travel without Lucas Verissimo as the defender continues his rehabilitation from a ruptured cruciate ligament.
Schmidt named an unchanged side at the weekend, with his side repaying their manager's faith in them by thrashing Arouca 4-0.
It seems unlikely the 55-year-old would feel the need to freshen things up, then, but he may look towards the bench in the second half providing the tie looks to be wrapped up.
FC Midtjylland possible starting lineup:
Olafsson; Dalsgaard, Sviatchenko, Juninho; Andersson, Onyedika, Sorensen, Dyhr; Dreyer, Kaba, Sisto
Benfica possible starting lineup:
Vlachodimos; Gilberto, Otamendi, Morato, Grimaldo; Luis, Fernandez; Neres, Silva, Mario; Ramos
We say: FC Midtjylland 1-3 Benfica
We can envisage another comfortable victory for Benfica to move themselves within one tie of the Champions League group stage.
They outclassed Midtjylland in the first leg and while it would be no surprise to see the Danish side score again, the visitors surely have too much firepower for them to handle.