After seeing Martin Demichelis sent off shortly before the hour mark, City slumped to a 2-0 defeat in the first leg of their last 16 tie with Barca at the Etihad Stadium last month.
While Lionel Messi opened the scoring from the penalty spot, having been fouled by Demichelis, it was Dani Alves who struck the hammer blow in stoppage time to hand City an almighty task to progress.
Barca have reached at least the final four of the competition in their last six attempts, lifting the trophy in 2009 and 2011.
Yet the Catalan giants come into Wednesday's game off the back of a surprise La Liga defeat to struggling Real Valladolid, which put a major dent in their domestic title ambitions.
The 1-0 loss at the Estadio Municipal Jose Zorrilla leaves Barca four points behind leaders Real Madrid, and sections of the Spanish press have been quick to express their discontent.
President Josep Maria Bartomeu even felt it necessary to defend the squad via his official Twitter account, stating: "We believe in them until the very end."
The defeat was Barca's second in three La Liga games but Bartomeu said he was confident the club's fans would get behind Gerardo Martino and his charges when City visit.
"It's normal for there to be some criticism, but the board, the members and the fans need to have confidence in these players. And even more so now that we're in the final stretch of the season," he told reporters.
While Barca have been below their best since winning in Manchester, Manuel Pellegrini's men have endured mixed fortunes.
The Chilean picked up his first trophy as City boss with victory over Sunderland in the League Cup before his side crashed out of the FA Cup on Sunday at the hands of old foes Wigan Athletic.
Despite suffering another shock loss to Wigan, their conquerors in last season's FA Cup final, Pellegrini is hopeful City can avoid exiting two competitions in the space of four days.
"It's difficult - of course it's difficult," Pellegrini told City's official website.
"However, I have no doubt that we are going to go to Barcelona thinking that we can do it and thinking we can beat them in Camp Nou and we try to have our revenge there.
"It (Barcelona) is a very good team with great players (but) I won with Villarreal in Camp Nou, I draw also with Malaga.
"If we can score a goal early then Barcelona may be a little bit more nervous. We go with a lot of trust to try to do it and if we are having a good day I am absolutely sure that we can do it."
