Manchester City may have considered getting the party poppers out when Nathan Redmond put the Saints in front - defeat for Liverpool would have confirmed Pep Guardiola’s side as champions.
They will have to wait for that though, as Takumi Minamino drew the visitors level before the break and Joel Matip then put them in front in the second-half.
It leaves City one point clear at the top of the table, with a goal difference that is six better than Liverpool’s. Aston Villa travel to the Etihad on Sunday, while Jurgen Klopp’s side host Wolves.
The Liverpool boss made nine changes to the side that won the FA Cup, with only Alisson and Ibrahima Konate keeping their places. Trent Alexander-Arnold, Virgil van Dijk, Mohamed Salah and Sadio Mane were all left out of the squad.
Southampton sat right off from the very first seconds, but it was the hosts who found the opening goal completely against the run of play.
Lyanco’s strong challenge on Diogo Jota was met by appeals for a free-kick from Liverpool, but the referee waved them away and the Saints found Redmond out on the left. He cut inside past Joe Gomez and rifled a brilliant effort into the far corner - VAR did not come to Liverpool’s rescue despite Klopp’s protestations.
That proved to be Southampton’s only shot in the opening 45 minutes. Roberto Firmino had the ball in the back of the net only for the linesman’s flag to go up for offside, before Minamino did pull the visitors level. Jota slid the ball through to his teammate, who spent time on loan at St Mary’s last season, and Minamino hammered into the top corner at the near post.
It was a low-key conclusion to the first-half, tainted for Liverpool by Gomez being forced off. Klopp revealed after the match that he is hopeful the injury is not too serious.
There was more of the same after the break - Liverpool piling numbers forward and Southampton just about holding firm. Jota dragged a shot inches wide of the far post, while Harvey Elliott could only find the side-netting from a tight angle.
Firmino was sensational on his first league start for six weeks, dropping deep and creating chances with a number of lovely touches and flicks. Curtis Jones got on the end of one and saw his low effort fly wide.
Midway through the second-half, the pressure told. An eighth Liverpool corner of the match was flicked on by Mohamed Elyounoussi into his own box, where Matip stuck out a head and found the corner of the net.
Southampton’s fans urged their side forward in the final 15 minutes, responding with boos as the team continued to sit back and let the visitors dominate possession.
There was no sign of any comeback and it was Liverpool who looked the more likely to get the next goal - Jones and Ibrahima Konate both had chances to put the match to bed.
Klopp’s side had done enough though and having reached three finals this season, with two trophies in the bag and a Champions League showpiece to come later this month, they’ve now taken the Premier League title race down to the final 90 minutes of the season.