It was a sloppy start from Arsenal and Southampton took full advantage as some woeful defending from Shkodran Mustafi allowed Shane Long to poke home for 0-1 in the 17th minute.
Goals from Pierre-Emerick Aubameyang and a double from Danny Welbeck was enough to give the Gunners all three points on what was a dramatic afternoon at the Emirates.
Only nine minutes before the final whistle, Danny Welbeck managed to score his second of the game, converting Alex Iwobi's ideal cross, handing Arsene Wenger's side the victory.
Substitute Charlie Austin equalised barely a minute after coming on, but with nine minutes left, Welbec headed in Alex Iwobi's cross.
At the Emirates Stadium, Southampton defender Jack Stephens was shown red in injury time when he reacted to Jack Wilshere tugging his shirt by pushing the Arsenal midfielder to the ground.
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Welbeck was the hero for the hosts, the forward on hand at the back post to nod home Alex Iwobi's deep cross for the victor just moments after he had failed to convert a glaring opportunity inside the six-yard box.
Iwobi, drifting dangerously between the lines, tested McCarthy himself after the restart but the Gunners remained vulnerable while their lead was slender and after Cech thwarted Pierre-Emile Hojberg, Mohamed Elneny cleared a Wesley Hoedt header off the line.
Danny Welbeck looked keen to add to his tally, but he missed an open goal initially. Long is not the most prolific but he showed a poacher's instinct in opening the scoring with his second goal of the Premier League campaign, and his willingness to run the channels was vital against opponents who dominated possession.
- Mark Hughes has now lost each of his 11 trips to Arsenal in the Premier League, only Harry Redknapp against Manchester United (15) is on a longer wait for an away win against an opponent in the competition.
Wenger did rotate his squad for Arsenal's fifth home game in a row, resting Mesut Ozil and Aaron Ramsey as Reiss Nelson was handed a first start in the Premier League. Other teams in the league are more clinical.