The much-changed Gunners, who have won the competition a record 14 times, fell behind midway through the first half and could not find a way back.
Ralph Hasenhuttl fielded a strong side at St Mary’s, with Danny Ings returning after a hamstring injury and a positive coronavirus test alongside former Arsenal forward Theo Walcott.
Mikel Arteta made seven changes from their 3-0 Premier League win against Newcastle on Monday.
Southampton, who had never previously beaten Arsenal in the FA Cup, were the brighter team in the first half in the winter sunshine on England’s south coast.
James Ward-Prowse rattled the crossbar from a swerving corner and Che Adams forced a fine save from Arsenal goalkeeper Bernd Leno.
Southampton got the reward their positive approach deserved in the 24th minute.
Mohamed Elneny gave away possession on the edge of his own box and the ball was worked to Kyle Walker-Peters on the right side of the Southampton attack.
The defender drilled it across the six-yard area and it was inadvertently turned in by Gabriel — the first time rejuvenated Arsenal had conceded since December 26 against Chelsea.
Ward-Prowse then struck a shot from distance that sailed wide and Ings hit a fierce volley that was blocked by Hector Bellerin.
Arsenal found their feet in the second half and Fraser Forster was forced to make a sharp save with his feet to keep out Eddie Nketiah’s deflected shot after a pass from Nicolas Pepe.
Arteta threw on forward Alexandre Lacazette to bolster his attack as Arsenal pinned Southampton back.
Lacazette was inches away from getting on the end of a teasing cross by fellow substitute Bukayo Saka as the minutes ticked away but Arsenal could not find an equaliser.
The exit will be a bitter disappointment for Arsenal, who have won the FA Cup four times in the past seven seasons — in sharp contrast to their toils in the Premier League.
Arteta’s side will return to Southampton for a league meeting on Tuesday, aiming to continue their fine recent run that has lifted them to 10th in the table.
(AFP/Punch)
