The Latics of League One have an excellent recent record in this competition, having won it in 2013, but are as big as 60/1 (61.0) with SportPesa to lift the trophy again this year.
The Saints, who were last FA Cup champions in 1976, are 11/1 (12.0) .
Maya Yoshida, Charlie Austin and Steven Davis are expected to miss out through injury for Southampton.
Wigan midfielder Shaun MacDonald’s season has been hampered by injury and will not play here.
Striker Will Grigg has seven FA Cup goals this season and was only risked for half an hour in the Latics' win over Bradford City on Wednesday night, recording an assist for the winning goal.
Saints for a clean sheet
Southampton have only conceded one goal in three FA Cup games; two of these came against Premier League opposition and the other against free-scoring Championship outfit Fulham.
Given that Wigan have drawn a blank at home to four League One sides since Christmas, the price of 7/5 (2.40) on a clean sheet for their top flight visitors appeals.
Preview and predictions
Southampton win to nil at 21/10 (2.10) is more tempting, though. Although Wigan are having an excellent season and should win promotion to the Championship, the experienced Hughes may make an instant impact for the Premier League side.Southampton win to nil 21/10 (2.1) with SportPesa