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.
What does it mean? Saints stun City to reach semis
This is a competition City have won in six of the past nine years, but they paid for the five changes made to their line-up, which included Walker as a centre-back in a back four.
City's substitutions made little difference as Southampton became only the third side after Man Utd (twice) and West Ham to get the better of Guardiola's City in the EFL Cup.
The Saints, who are three points from safety in the Premier League, will join Man United, Newcastle United and Nottingham Forest in the semi-final draw later on Wednesday.
Shot-shy City shown up
Despite bringing on their big guns, plus having the likes of Phil Foden, Jack Grealish and World Cup winner Julian Alvarez in their side, City did not test Gavin Bazunu once.
It is the first time City have failed to hit the target in a game this campaign, while their seven shots in total is also a low in what was a terrible display from Guardiola's men.
Mara makes his mark
Walker has proven he is a versatile defender, but he looked uncomfortable playing as a centre-back in a four-man defence and was hooked at half-time.
That was after Mara beat the England international to a right-sided cross for a crucial opening goal, with that his first for the club on what was his 16th outing.
What's next?
City have that Manchester derby showdown to come on Saturday, while Southampton travel to fellow strugglers Everton later that day in a huge relegation showdown.
