The Gunners were unchanged from their vital 2-1 win over Manchester City five days earlier, and would have leapfrogged Leicester at the summit of the Premier League with a win.
Saints took the lead through the unlikely source of Cuco Martina, who was starting his first Premier League game for the hosts, after the defender found the corner of the goal with a superb long-range half-volley.
Shane Long added a second from close range in controversial fashion after Arsenal claimed he had fouled Laurent Koscielny in the build-up, before Jose Fonte headed home Southampton’s third from a corner.
It was 3-0 with just over 20 minutes remaining as the unmarked Fonte headed home from point-blank range as Koscielny failed to deal with his opposite number’s aerial presence.
Mesut Ozil’s touch under Stekelenburg nearly crept over the line with 10 minutes remaining, but Southampton continued to press for another goal as Long got the better of both Koscielny and Mertesacker with his pace.
Long hit the post while one-on-one with Cech with a minute remaining, but got his second and Saints’ fourth from an identical angle in stoppage time, driving the ball under the goalkeeper to round off Arsenal’s humiliation.
The result leaves Arsenal two points off leaders Leicester, while Saints stay 12th after their first win since November 7.