Manchester City suffered a big blow ahead of an important week as a Sadio Mane hat-trick inspired Southampton to a 4-2 Premier League win at St Mary's Stadium.
Manuel Pellegrini had complained pre-match about having to play on Sunday ahead of Wednesday's Champions League semi-final trip to Real Madrid, and the Chilean duly omitted a number of first-team regulars from his starting line-up.
Sergio Aguero, Bacary Sagna, Gael Clichy and Fernando watched the entire game from the bench, while Kevin De Bruyne was left out entirely.
Southampton sensed the chance of an upset and deservedly took the lead through Shane Long, before Mane scored a fine effort three minutes later to cap their first-half dominance.
Kelechi Iheanacho grabbed a lifeline just before the break and City responded well early in the second half, but Mane bundled the ball home after a scramble in the penalty area to restore Saints' two-goal lead before completing his treble with a good low finish 10 minutes later.
Iheanacho bent in a fine consolation, but Southampton move to within two points of the top six, while City - who host third-placed Arsenal next Sunday - must continue to look over their shoulders towards Manchester United, who could close to within a point of fourth if they win their game in hand.
Southampton set about pressing Pellegrini's much-changed line-up from the outset, with Mane testing Joe Hart from 25 yards out with just two minutes on the clock.
Long rippled the side-netting from distance and Raheem Sterling shot straight at Fraser Forster from 10 yards after Iheanacho had robbed Virgil van Dijk and teed up the England winger.
That stop proved pivotal as Southampton took the lead midway through the half. Cuco Martina's ball over the top was hooked towards the penalty spot by Dusan Tadic, and Long arrived ahead of Nicolas Otamendi to prod low past Hart.
Saints were in complete control and doubled their lead three minutes later with an outstanding counter-attack goal. Victor Wanyama released Tadic down the right, and his perfectly weighted through-ball between City's static defenders allowed Mane time and space to sweep low past Hart.
City had barely mustered a threat but they grabbed a lifeline a minute before half-time, as Iheanacho nodded past Forster from close range after Southampton had failed to clear Samir Nasri's low cross.
Iheanacho was undoubtedly City's brightest player and he brought another low save from Forster early in the second half after combining well with strike partner Wilfried Bony on the edge of the area.
But City were dealt a killer blow on 57 minutes as Mane restored Southampton's two-goal cushion, reacting quickest at the far post after Hart had just managed to keep Van Dijk's header from crossing the line.
Hart tipped Van Dijk's overhead kick just over the crossbar but he could do nothing to deny Mane his hat-trick. The Saints winger bagged his 10th league goal of the season as he raced onto Tadic's low pass before slotting into the corner at the near post.
Iheanacho curled a brilliant strike beyond Forster in the closing stages but the game was up for City, who now turn their attentions to a Champions League showdown in the Spanish capital.