It will be the 13th time the heavyweight clubs have faced off in a competitive fixture, with Barca winning five and losing three of those.
The Catalan giants have come out on top in each of the last three encounters, though, including a 1-0 win in the first leg at Old Trafford.
Here, Sports Mole selects its strongest combined XI from both squads, using only players available for Tuesday's match.
Arguably the toughest choice of all to make is in goal. David de Gea is widely considered by many to be the best goalkeeper in the world, but there is a case to be made for opposite number Marc-Andre ter Stegen, who has been consistently brilliant for a few years. For his ability to produce out-of-this-world saves, though, De Gea gets the nod.
Man United are not blessed with many full-back options for Tuesday's match as Luke Shaw, their only consistent performer, misses out through suspension. Diogo Dalot has huge potential but has played more as a winger in his debut campaign at Old Trafford, while Ashley Young and the lesser spotted Antonio Valencia are nowhere near the standards of opponents Sergi Roberto and Jordi Alba. It says an awful lot about Barca's strength in depth that Roberto's place in the starting lineup on Tuesday is not assured as Nelson Semedo is also available for selection.
At the back, Gerard Pique has gone from strength to strength since leaving Man United more than a decade ago. The Spanish defender has formed a solid partnership with Clement Lenglet, who has filled in well for injury plagued Samuel Umtiti. As good as Lenglet has been, Victor Lindelof has been one of United's best performers since Christmas time and would not look out of place in a side with Pique.
Using a three-man midfield that both sides favour, there is a place for Paul Pogba on the left, where he has thrived since Ole Gunnar Solskjaer was appointed in December. Just when the Frenchman had started to go off the boil again, he showed great composure to tuck away a couple of penalties in United's weekend win against West Ham United. To the right of him, Sergio Busquets continues to anchor the midfielder better than anyone on the planet and Ivan Rakitic - despite strong rumours linking him with a move away - has been superb of late.
As ever, Lionel Messi is the first name on the teamsheet as he continues to seemingly break records on a weekly basis. Luis Suarez, despite having his critics, has again showed why he is so highly valued by Barcelona this term by knocking in another 20 La Liga goals, seeing him selected over Romelu Lukaku. There is a place up for grabs on the left of the front three, as Ousmane Dembele has endured another frustrating campaign and Philippe Coutinho has also struggled to hold down a regular starting spot. Marcus Rashford, by comparison, has showed further glimmers over the past few months of why he has been tipped to go to the very top, so he completes our side.