Philippe Coutinho opened the scoring for Liverpool with a lovely curling strike from distance, and Daniel Sturridge doubled the visitors' advantage before half-time.
However, Mane's introduction changed everything. First Simon Mignolet saved a penalty early in the second half, before Mane redeemed himself for the miss, scoring a wonderful goal.
Southampton pushed for an equaliser and found it seven minutes before the final whistle, as Graziano Pelle pulled his team level, and Mane added a winner just minutes later to hand the Saints the unexpected win.
As shared by the club's official Twitter account, Sturridge and Divock Origi started up front for the Reds, while Jon Flanagan wore the captain's armband. James Milner missed the match through a suspension, and Roberto Firmino was also absent:
The match started at an incredible pace, with both teams looking to attack early. Southampton wanted a penalty after just seven minutes, as Shane Long was felled inside the box, but the Saints' calls fell on deaf ears.
Long was active early, and the hosts looked the more dangerous of the two sides during the first 10 minutes, but Liverpool gradually got a grip on the midfield area and started pushing Southampton back into their own half.
Sturridge put Fraser Forster to work with a shot from distance, and one minute later, Coutinho had the ball in the net. Adam Lallana stole the ball in midfield and fed it to the Brazilian, who cut inside and produced a stunning curling shot.
Per the Premier League's official Twitter account, Coutinho has a knack for scoring these kind of goals at St. Mary's:
Liverpool's official Twitter account noted Lallana has been in stunning form of late:
The early deficit seemed to shock the hosts, and Liverpool pressed their advantage, doubling their lead five minutes later. Origi used his speed and strength to create some space before laying the ball off to Sturridge, who took a smart touch before blasting home.
Bleacher Report UK was impressed:
Joe Allen nearly made it 3-0 shortly after, but Forster did well to deny the Welshman after he had burst through on goal. He was denied by the linesman a little later, as Mamadou Sakho was deemed to be offside and sufficiently hindering Forster for the official to blow the whistle.
James Pearce of the Liverpool Echo thought Allen was unlucky:
Liverpool continued to look the better side, and Southampton's quick start was nothing but a distant memory as half-time drew closer. The hosts were unable to mount any resistance until the final minutes of the half, but the Reds comfortably weathered the storm and left the pitch with a two-goal lead.
Squawka Football shared the half-time stats:
Martin Skrtel was introduced at half-time, and one of his first contributions of the second half was giving away a penalty by pulling down Pelle. The contact was light, but the official pointed to the spot, regardless.
Substitute Mane stepped up to take the spot-kick, but Mignolet chose the right side and saved, keeping the two-goal lead intact. Per Squawka Football, stopping penalties is becoming something of a specialty of the Belgian:
Saints manager Ronald Koeman had clearly given his team a stern talk, as the hosts came out with plenty of attacking intent to start the second half.
Hero Mignolet nearly gifted the hosts a goal when he was caught away from his goal, but fortunately for the Belgium international, Pelle's header failed to hit the target, per Pearce:
Southampton's pressure was increasing, and the Reds were struggling to keep the hosts out of the area. Oriol Romeu came very close to scoring with a fantastic shot from long range, before Mane redeemed himself for his penalty miss, passing Sakho before slotting home.
Per World Soccer Talk, the goal had been coming:
Manager Jurgen Klopp introduced Christian Benteke for the Reds and reorganised his team, and the changes seemed to help. Southampton's pressure seemed to lift, and Origi in particular started to find space to exploit on the counter-attack.
Benteke perhaps should have scored after a wonderful pass from Lallana, but the Belgium pushed his shot just wide of Forster's goal.
His mistake proved costly, as Pelle fired home a wonderful strike inside the final 10 minutes to pull his team level. All the momentum was now with the hosts, and just two minutes later, Mane bagged his second to complete the comeback.
Pearce couldn't believe it:
Neither could Bleacher Report UK:
The Reds pushed up the pitch in search of a late equaliser, and Coutinho tried his luck from distance again, but his shot sailed over the bar. That would be the final chance of the match, as Southampton held on for the win.
Per Sky Sports, Klopp rued the chances his team missed:
As shared by the Premier League's official Twitter account, Koeman was more than a little excited about the comeback:
The win puts some distance between Liverpool and Southampton, who now sit in seventh place in the standings. The race for the UEFA Europa League tickets remains as tight as ever, and Saints took a major step forward on Sunday.