An horrendous mistake from Saints goalkeeper Artur Boruc help set Premier League leaders Arsenal on their way to a 2-0 win at the Emirates Stadium.
The Poland goalkeeper made a complete mess of his footwork when caught in possession by Olivier Giroud in the six-yard box on 22 minutes.
Arsenal never looked in danger of relinquishing their advantage and settled the game with a late penalty from France striker Giroud to take full advantage of Liverpool's draw in the Merseyside derby at Everton and move four points clear at the top.
Kick-off was delayed by 15 minutes following problems on the London transport network.
Saints were thumped 6-1 here last season, a result which hastened the end of Nigel Adkins and the appointment of Mauricio Pochettino.
However, the visitors - unbeaten in eight league games, with just one defeat - were certainly not looking for a repeat result this time around, with attention very much fixed on looking up the table.
Arsenal, though, fashioned the first opening after 11 minutes.
England midfielder Jack Wilshere, showing no signs of his involvement at Wembley over the international break, charged into the right side of the penalty area and looped the ball over Boruc. However, it dropped onto the inside of the far post before bouncing back into the arms of the grateful Saints keeper.
The Gunners continued their patient build-up and unlocked Southampton's defence again on 17 minutes, only to be denied by the same woodwork.
Mesut Ozil's cross was flicked goalwards by Aaron Ramsey, but, with the keeper beaten, the ball shaved the outside of the right post.
There was, though, no saving the Saints stopper when he gifted Arsenal the lead on 22 minutes.
Boruc - beaten by a long punt from Stoke goalkeeper Asmir Begovic earlier this month - made a complete hash of his attempted dragbacks when dwelling on the ball under pressure from Giroud.
The France striker promptly robbed the Pole in the six-yard box, and slotted home his sixth Premier League goal into an empty net.
To their credit, Southampton looked for a response - with referee Mark Clattenburg aggravating the home support with some of his decisions.
Arsenal goalkeeper Wojciech Szczesny remained alert to tip over a dipping 18-yard effort from Saints captain Adam Lallana, fresh from his full England debut over the international break.
On 40 minutes, the Poland international then produced a fine one-handed save to deny a well-executed half-volley from Jay Rodriguez, after the new England cap collected the ball on his chest before drilling it goalwards from 15 yards.
Dutch defender Jos Hooiveld, in for the ill Dejan Lovren, was booked for a high boot on Giroud.
Southampton made a change at the start of the second half as defender Luke Shaw was replaced by Steven Davis.
The visitors were lively again, with Lallana driving a 20-yard effort goalwards following another swift counter-attack.
The Saints skipper was replaced by £15million forward Pablo Osvaldo on 55 minutes.
Arsenal continued to press for a second goal, but found little space behind the well-drilled Southampton defence.
With 20 minutes left, Theo Walcott, out since September 18 with an abdominal problem, came on for Santi Cazorla.
Arsenal were then forced into another change when Mikel Arteta hobbled off with what looked like an ankle problem, and Czech playmaker Thomas Rosicky came on.
Southampton refused to give up and there were some nervy moments for the home crowd during the closing stages.
Walcott, returning against his former club, flashed an angled drive across goal.
Arsenal were awarded a penalty on 86 minutes when Germany defender Per Mertesacker, who missed the defeat at Manchester United before the international break with a virus, had his shirt pulled by Jose Fonte.
Giroud made no mistake from the spot, as Arsenal provided the required response to keep themselves clear of the chasing pack.
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