The Catalan giants, knocked out by Atletico Madrid, Juventus and Roma at this stage in the previous three campaigns, picked up a slender victory at Old Trafford through a Luke Shaw own goal.
Barca now have to see the job through on home soil against a United side boasting away wins at Juve and Paris Saint-Germain in this season's competition.
Here, Sports Mole looks at how Ernesto Valverde may set out his side on Tuesday evening.
Valverde rested several key members of his first-team squad for Saturday's goalless league draw against bottom side Huesca with this return match in mind.
Rakitic has been suffering from an illness bug but should be fine to play a full part against United, and Messi has also been given the all-clear to play after suffering a facial injury at Old Trafford.
Ousmane Dembele made a welcome return from the bench against Huesca, but that was his first appearance in a month and it is unlikely that Valverde will select him over Philippe Coutinho for this huge clash.