Nicholas Pepe cancelled out Stuart Armstrong’s early opener before Bukayo Saka broke the deadlock approaching half-time and Alexandre Lacazette made it a comfortable win for the Gunners.
Both Armstrong and Pepe scored inside the opening eight minutes, which looked set to produce a fiery outing between the two who met just three days ago.
But Saints would manage just four more shots on target, as a makeshift back-line struggled with the strength and speed of Pepe and Saka.
Southampton took the lead on a sublime goal after Armstrong volleyed in James Ward-Prowse’s corner kick on three minutes.
Pepe then shrugged off Jan Valery to latch onto Granit Xhaka’s perfectly weighted through ball before dispatching a shot beyond the reach of Alex McCarthy in the eighth minute.
McCarthy was then caught out in the build-up to Arsenal’s second goal, with Saka taking one touch to round the goalkeeper to slot into an empty net six minutes before half-time.
Lacazette made it 3-1 on 73 minutes following a great bit of play that saw former Saints man Cedric swing the ball from left to right before Saka picked out the forward in the box.
Ward-Prowse was close to a late consolation, but he couldn’t add to his tally of free-kick goals when he forced a diving save from Bernd Leno nearing full-time.
The result leaves Saints down in 11th place on 29 points from 19 games while Arsenal’s resurgence of late has seen them climb into eighth with 30 points.
Southampton (4-4-2): McCarthy; Vokins (Redmond 67), Stephens Bednarek, Valery; Armstrong, Ward-Prowse, Diallo, Walcott (Adams 74); Ings (N’Lundulu 74), Adams
Unused subs: Forster (GK), Long, Ferry, Ramsay, Jankewitz, Chauke
Goals: Armstrong (3)
Bookings: Watts (90)
Arsenal (4-2-3-1): Leno; Cedric, David Luiz, Holding, Bellerin; Xhaka, Partey (Elneny 78); Pepe (Wilock 90+2), Smith Rowe (Willian 72), Saka; Lacazette
Unused subs: Ryan (GK), Chambers, Maitland-Niles, Gabriel, Nketiah, Martinelli
Goals: Pepe (8), Saka (39), Lacazette (72)
Bookings: Bellerin (19), Pepe (70)