United launched an unforgettable comeback to beat Paris Saint-Germain on aggregate in the last 16, and they will be hoping for a similarly-sized upset over two legs against the La Liga leaders.
Ole Gunnar Solskjaer's side have lost three of their last four outings, though, whereas Barcelona boast a 16-match unbeaten streak that has taken them to the brink of a second successive domestic title and kept them on course for the treble.
Here, Sports Mole selects its strongest combined XI from both squads, using only players available for Wednesday's match.
Two of the world's best goalkeepers will be on show in this tie, with Marc-Andre ter Stegen having firmly established himself in the very top echelon with his performances over the past year or two. David de Gea remains arguably the very best of the lot, though, and narrowly earns the gloves in this team as a result.
It is all Barcelona in front of him, though, and in truth there was not a great deal of competition. Luke Shaw has rediscovered his best form under Solskjaer but remains some way behind the level of Jordi Alba, while on the opposite flank Sergio Roberto is an easy pick ahead of Ashley Young and Diogo Dalot.
Former United man Gerard Pique is one of the world's best central defenders and comfortably earns his place ahead of Phil Jones, Chris Smalling, Eric Bailly or Victor Lindelof, and Clement Lenglet has taken advantage of an injury to Samuel Umtiti to nail down a regular starting spot in the Barcelona team this season.
When it comes to the world's best in their positions, Sergio Busquets also comes into the conversation in defensive midfield, and he sits in front of that all-Barcelona defence ahead of the United option Nemanja Matic.
The Red Devils do finally provide an outfield representative in Paul Pogba, who has been linked with Barcelona in the past and has shown much more of his world-class talent since the departure of Jose Mourinho in December. The PSG comeback in the last round was all the more impressive in that it came without the suspended Frenchman.
Ander Herrera is the main United contender to complete the midfield, but most of the competition comes from Barcelona with Arthur, Philippe Coutinho and Arturo Vidal all missing out to Ivan Rakitic - a man linked with a move to United this summer.
The easiest pick in the team - or any team, for that matter - is the timeless Lionel Messi, who continues to defy belief with his relentless form. United's chances may rest largely on how well they are able to tame the Argentine, who has scored in a Champions League final between these two sides.
For all of United's attacking talent, the centre-forward role is another relatively straightforward choice with former Liverpool man Luis Suarez - who has his own chequered history against United - leading the line ahead of Romelu Lukaku.
Marcus Rashford is another contender for that central striking role, but he is pushed out to the left for this XI in a position with plenty of options, including Anthony Martial, Coutinho, Malcom and Ousmane Dembele, the latter of whom faces a race against time to be fit for this match.