Shane Long also got on the scoresheet for the Saints
Sadio Mane scored a hat-trick for Southampton as the Saints saw off Manchester City 4-2 at St Mary's.
City, who face a Champions League second leg semi-final match against Real Madrid in midweek and started without Sergio Aguero, Kevin De Bruyne and captain Vincent Kompany, were aiming to return to third in the Premier League table.
But the 4-2 defeat means City will have to look over their shoulder to neighbours Manchester United who sit fifth, four points behind the final Champions League qualification place but with a game-in-hand to reduce the gap to fourth.
Ireland striker Shane Long gave Southampton the lead on 25 minutes to convert his fourth goal in five games, before Mane got his first by slotting in a Dusan Tadic pass three minutes later.
Man City gave themselves hope heading into half-time as youngster Kelechi Iheanacho continued his impressive goalscoring form with a goal to pull it back to 2-1 on 44 minutes.
But Mane scored twice after the break to stretch the Saints' lead again, before Iheanacho (19) scored his seventh of the season to leave the scoreline at 4-2.