SAINTS pushed English champions Liverpool all the way in the Carabao Cup third round, but £210million worth of strikers won it 2-1 for the hosts.
Will Still's side produced a much-needed positive performance against all the odds at Anfield but were unable to force the game to a penalty shootout.
Leo Scienza missed a glorious chance to open from close range after Adam Armstrong's lob hit the crossbar and bounced to him in the box.
Alexander Isak, for whom Liverpool smashed the British transfer fee record this month, punished that seconds later with his first Reds goal.
Cup goalkeeper Alex McCarthy was continuing his push for a starting berth in the league before his loose pass handed the home side the chance.
Shea Charles hit his first Saints goal in the 76th minute to level, but Hugo Ekitike won it 10 minutes later, before being issued a second yellow card for his celebrations.
Saints tried to make their man advantage count in six minutes of added time, but were unable to fashion a meaningful chance to extend their cup run.
Southampton reacted much better to going behind in the first half today. Frustrating not to get to penalties. They have to play that well against Boro on Saturday. #SaintsFC pic.twitter.com/Tn0yOKY6hD
— George Rees-Julian (@rees_julian) September 23, 2025
This was the fifth time Saints have visited Anfield since November 2021, and on each occasion a different manager has led the St Mary's side.
Still will have known that all four of the previous bosses were also beaten, with Saints last avoiding defeat in a 0-0 draw under Claude Puel in May 2017.
Jack Stephens is the only surviving player from that team, although Adam Lallana - now in the dugout for Saints as a coach - appeared for the hosts.
The skipper was not in the squad that travelled this time around, and Still named nine changes to his starting team that was beaten 3-1 at Hull City.
The boss handed out full debuts to full-back Elias Jelert and winger Scienza, and he opted for a shape change with a fully rotated three-man defence.
Southampton fans at Liverpool! 👏
🟡🔵🟡🔵#SaintsFC pic.twitter.com/W7EIpMgBq8— Alfie House (@AlfieHouseEcho) September 23, 2025
McCarthy was also restored to the lineup, having kept a clean sheet in round two, and made a top save to deny Isak inside the first 60 seconds.
Aside from that, Saints produced an impressive first-half show, taking advantage of facing a team not determined to just sit in a low block and defend.
Ryan Manning whipped a cross that only evaded Cameron Archer by a whisker, and Nathan Wood was there to get first contact on balls in his box.
Wood and Ronnie Edwards both showed they could step forward in possession, creating an extra man in attack and freeing up the tidy Caspar Jander.
Scienza was lively and creative, while Jelert looked composed and forward-thinking. Armstrong forced Giorgi Mamardashvili into a decent save.
That was all undone in a few ruthless seconds. Saints should have taken the lead in the 42nd minute, but Scienza headed wide with the goal at his mercy.
Archer's perfect pass to meet Armstrong's perfectly timed run saw the number nine chip over Mamardashvili - but onto the crossbar and out.
With the keeper nowhere to be seen, Scienza arrived at the bouncing ball and tried to direct it past Giovanni Leoni, but directed it wide of the left post.
The ball was in McCarthy's net 30 seconds later, as his loose pass to Joshua Quarshie was snatched by Federico Chiesa and fed across the box to the grateful Isak.
Liverpool made a change during the interval. Ekitike, worth £79m, replaced £130m Isak, though Chiesa thought he had scored but was well offside.
But Charles was not when he fired in from inside the six-yard box after Wataru Endo's poor clearance of a Manning corner fell to Quarshie in the box.
With 14 minutes still on the clock, both teams had designs on winning. But Liverpool struck with Ekitike, handed a chance on a plate by Chiesa in the 85th minute.
However, the Frenchman was then sent off for his second yellow card due to taking his shirt off as part of his celebrations, reducing the Reds to 10 men.
He would still end the night the hero, winning the match for Liverpool on their return to the Carabao Cup, and eliminating Still's side despite their efforts.
Liverpool: Mamardashvili; Frimpong, Gomez, Leoni (Kerkez, 80), Robertson; Endo, Jones (Bradley, 57), Nyoni; Chiesa, Ngumoha (Danns, 74), Isak (Ekitike, h-t).
Unused subs: Woodman, Williams, Gordon, Morrison, Pilling.
Booked: Ekitike.
Sent off: Ekitike.
Saints: McCarthy; Edwards (Stewart, 87), Wood, Quarshie; Jelert (Fellows, 87), Jander (Charles, 50), Downes, Manning; Armstrong, Scienza (Robinson, 61), Archer (Downs, 50)
Unused subs: Long, Harwood-Bellis, Matsuki, Fraser.
Booked: Archer, Manning.
Referee: Thomas Bramall.
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