Tranmere defender Marlon Broomes should be fit after coming through a midweek reserve game following a calf injury.Fellow defenders Zoumana Bakayogo (foot), Tim Cathalina and Max Blanchard are also absent, while striker Ian Thomas-Moore also misses out.
Southampton welcome back captain Dean Hammond, who has missed the last two games with a calf injury.
Midfielder Adam Lallana (leg) is unlikely to be risked, while winger Lee Holmes (knee) is a long-term absentee.
Tranmere manager Les Parry told BBC Radio Merseyside: "Southampton is a fantastic club and too big for our division, but so are Sheffield Wednesday, Charlton and Huddersfield.
"But at the end of the day, they're in League One and it's great to play them.
"I don't like talking about luck, but switching off is an area we've got to look at.
"There's 90 minutes in a game, we've got to concentrate for 90 minutes and do the simple things well."
Source: BBC Sport
Source: BBC Sport