Pep Guardiola's decision to name an understrength starting line-up backfired as Manchester City were beaten 2-0 by Southampton in Wednesday's EFL Cup quarter-final tie.
Erling Haaland, Kevin De Bruyne, Bernardo Silva and Ederson were among City's substitutes at St Mary's with Saturday's league game against Manchester United in mind.
That proved costly as Sekou Mara and Moussa Djenepo – profiting from some poor Stefan Ortega positioning – had the Premier League's bottom side two goals up at half-time.
The arrivals of De Bruyne and Erling Haaland gave City slightly more of an attacking edge, but they could not find a route back into the game as they suffered a shock exit.
Ortega did well to turn aside Duje Caleta-Car's low effort, but there was no stopping Mara's first-time shot after the forward got in front of Kyle Walker to convert Lyanco's cross.
Southampton had a second five minutes later when Djenepo cut inside, spotted Ortega well off his line and executed his lobbed finish from 30 yards to perfection.
Guardiola took action at the break by making a triple substitution, with Haaland also brought on 10 minutes later, but City's response did not arrive on the south coast.
The visitors failed to register a single shot on target as they lost for the fourth time in 28 matches this season, and the first time since the World Cup break.