Dejan Lovren's header eight minutes into the second half was the difference as the league leaders were beaten for the first time this campaign.
The Croatia international defender met Adam Lallana's left-wing corner and, despite close attention from his marker, diverted the ball home with the angle against him.
The hosts made three changes to the side who drew 2-2 with Swansea City on Monday, Iago Aspas replacing the injured Philippe Coutinho and Daniel Agger and Kolo Toure coming in for Andre Wisdom and Jose Enrique in the defence. Southampton manager Mauricio Pochettino named an unchanged side from the team that drew 0-0 with West Ham.
|By Tom Marshall-Bailey
Liverpool's unbeaten start to the Premier League season came to an abrupt halt as a Dejan Lovren-inspired Southampton side secured a deserved 1-0 success at Anfield.
The hosts looked toothless in attack without the likes of Philippe Coutinho and Luis Suarez and Brendan Rodgers will be equally concerned by some of his side's defensive work as the Saints got at the Reds' back line too easily and frequently.
Lovren stooped to head home from the equally impressive Adam Lallana's corner from the left as Mauricio Pochettino and his men got back to winning ways.
After 21 minutes, Boruc pulled off a save of much higher quality, flying to his right to tip away a Steven Gerrard free kick that was destined for the top corner following Jose Fonte's foul on Aspas.
As the pace of the game intensified, Rickie Lambert wasted a golden chance to open the scoring in the 27th minute, swivelling on a loose ball eight yards from goal but failing to make a true connection, his shot looping up into Simon Mignolet's arms.
The visitors were lucky not to concede a penalty five minutes later when Daniel Sturridge looked to have been tripped as he cut inside Lovren, although the referee waved play on.
Boruc once again came to his side's rescue nine minutes before the break when he denied Victor Moses at the near post after the Nigeria international had weaved his way past two defenders on the left-hand side.
On the stroke of half time, Sturridge met Gerrard's cross from the right but the ball cannoned off the striker's shoulder rather than his head and looped onto the roof of Boruc's net.
Mignolet put his side under pressure two minutes after the break when he tried to play the ball out from the edge of the box but, as Southampton won possession, the Belgium international raced off his line to deny Lallana and redeem himself.
In the 53rd minute, it was the visitors who took the lead when Lovren met Lallana's corner and, despite being off balance, he powered his header between the diving Mignolet and Gerrard on the line.
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The hosts were stunned into action, Boruc denying Gerrard from another free kick, this time low to his left in the 59th minute.
Southampton almost extended their lead shortly after, with substitute Steven Davis riding three challenges on a charge into the box before being denied by the legs of Mignolet, the goalkeeper reacting quickly to tip away the rebound as Davis looked to pounce.
Sturridge wasted a good opportunity with 12 minutes left when, after finding himself in plenty of space on the right, the England forward curled the ball high over the crossbar.
Liverpool continued to press but substitute Luis Alberto's weak effort in the 87th minute was blocked as Southampton held on to seal the points.