Much like he did for City's FA Cup thumping of Chelsea, Pep Guardiola benched a number of key players for the clash with Erling Haaland, Kevin De Bruyne, Rodri, Bernardo Silva, Ederson and Riyad Mahrez among those not starting.
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And it's a decision he lived to regret with Southampton dumping them out.
Nathan Jones' men took the lead as Sekou Mara expertly swept home a cross from the right on 23 minutes.
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And just five minutes later the eight-time winners of the competition went 2-0 down when Moussa Djenepo lobbed City stand-in goalkeeper Stefan Ortega from distance.
It was a well executed strike from Djenepo, however, questions were asked about Ortega.
"He's got it out his feet, and he's got so much loft on it, you thought it was going way over the goal. The goalkeeper's position was misleading slightly. City now have a real fight to stay in this game," Stuart Pearce said on commentary for talkSPORT.
"As a goalkeeper you can't expect to be on your penalty spot when a player has the ball 30 yards from goal," Chris Iwelumo said on commentary for talkSPORT 2.
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"That's a really poor starting position, but take nothing away from Djenepo," former West Brom, Sunderland and Wolves player Don Goodman said on commentary for Sky Sports.
Saints fans may have expected a City onslaught in the second half but the away side amazingly failed to manage a shot on target in what was a lacklustre performance.
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Southampton take on Newcastle in the semi-finals, while Manchester United meet Nottingham Forest.