The midfielder misses the clash at St Mary’s Stadium with an ankle injury, and is also doubtful for the Gunners’ Premier League match against Crystal Palace on Sunday.
Arsene Wenger admitted on Monday that Wilshere was "a doubt" for the Southampton trip after suffering the latest in a long line of ankle problems in Arsenal’s FA Cup win over Coventry City last Friday.
However, it is not expected at this stage that Wilshere will face an extended spell on the sidelines.
Arsenal's preparations for the Saints match have also been hampered by several first-teamers missing training on Monday through illness, but it is unlikely to have a significant effect on the composition of the starting XI.
Wenger’s midfield is reinforced on Tuesday night by the long-awaited return to the squad of Aaron Ramsey and Mikel Arteta. Ramsey has been out since Boxing Day with a grade two thigh strain, while Arteta has not figured since the Cup win over Tottenham on Jan. 4.
Captain Thomas Vermaelen is also in the matchday squad of 18 after overcoming a knee problem that has kept him out since the Spurs game.