Arsenal had won just three times in the last nine encounters against Southampton in all competitions prior to kick off.
But an under-strength Saints side were put to the sword by the returning duo of Danny Welbeck and Theo Walcott.
Welbeck, in his first start since May, scored twice before Walcott scored his fifth hat-trick in an Arsenal shirt to send the Gunners into the FA Cup fifth round.
Theo Walcott scored his fifth hat-trick in an Arsenal shirt
Theo Walcott now has 99 goals for Arsenal in all competitions
The former Southampton youngster hasn't played in Arsenal's last seven matches took his tally for the season to 14 goals.
"Southampton tend to be our bogey side but from the word go we were ready," said Walcott.
Arsenal player ratings against Southampton
Sat, January 28, 2017
Click through the gallery for the Arsenal player ratings against Southampton
1 of 11
GK: David Ospina – 6: A couple of casual moments but generally solid
"We came out of the blocks running and Danny Welbeck came back with a bang.
"We created a lot of chances and it was nice to have the clean sheet.
"Southampton will always be in my heart I have some great memories here, they are a strong team and I will cheer them on in the EFL Cup final."