Liverpool (89 points) trail City (90 points) by a single point entering the final day, but would need their rivals to drop points in order to pinch the title away.
Saints, meanwhile, continue to limp towards the finish line having picked up third straight defeat and fourth in their last five outings.
Looking at the larger picture, Southampton has picked up just five points (1W, 2D) from their last 11 matches.
Still, the South Coast club are safe for another year in the top-flight after results fell their way last weekend. It is a three team race — Burnely, Leeds and Everton — for the final relegation spot.
Nathan Redmond fired Saints to a dream start when he converted a sensational effort from the edge of the box, helped on by the toe of James Milner.
After Lyanco spearheaded the counter-attack by winning a controversial challenge on the edge of his own box, Nathan Tella picked out the Redmond who was able to cut inside before beating Alisson to the far corner.
It was Redmond’s first Premier League goal in 25 appearances — the last coming against Burnely in April 2021.
But the momentum was short lived as former Saints loanee Takumi Minamino drew Liverpool level with a right-footed effort that caught out Alex McCarthy at the near post with 27 minutes gone.
It was a deserved equaliser for the visitors as Jota had seen a goal correctly ruled out for offside in the 18th minute. Liverpool, however, had been threatening with their press.
McCarthy, who was making his return after being on the sidelines since December, was one of four changes to the Southampton side.
Following the goal, Liverpool took control of the match and had two clear cut chances following the restart.
Diogo Jota shot wide of the far post in the 48th minute, before Harvey Elliott tickled the side netting from a tight angle after being played in down the right just moments later.
Joel Matip made it 2-1 to Liverpool from a 67th-minute corner-kick, capitalising on bad luck from Kyle Walker-Peters whose attempted headed clearance came back off his opponent’s head and looped into the net.
Southampton (4-4-2): McCarthy; Salisu, Stephens, Lyanco, Walker-Peters; Redmond, Diallo (Romeu 71), Ward-Prowse, Elyounoussi; Broja (Adams 82), Tella (Armstrong 71)
Unused subs: Caballero (GK), Djenepo, Valery, Bednarek, Long
Goals: Redmond (13)
Bookings: Tella (69), Stephens (74)
Liverpool: Alisson; Tsimikas, Konate, Matip, Gomez (Henderson 45); Jones, Milner, Elliott (Origi 65); Diogo Jota, Firmino (Keita 83), Minamino
Unused subs: Kelleher (GK), Oxlade-Chamberlain, Thiago, Luis Diaz, Keita, Robertson, Williams
Goals: Minamino (27), Matip (67)