Capable of playing at centre-back, full-back, holding midfield or on the wing, Manning may be central to any selection combination Russell Martin chooses against the Blues.
The boss will be without Taylor Harwood-Bellis, Flynn Downes and Tyler Dibling due to suspension on Wednesday evening.
Adam Lallana and Will Smallbone remain out with injuries, Lesley Ugochukwu is ineligible against parent club Chelsea while Jan Bednarek and Paul Onuachu remain fitness doubts.
That leaves Martin with several gaps to plug, particularly in midfield, where Mateus Fernandes and Joe Aribo remain the only natural options.
Manning was trialled in holding midfield during pre-season as they assessed his options heading into the Premier League campaign.
READ MORE: 'Best version of yourself' - Manning happy to play anywhere for Saints this season
The Galway native is willing to play anywhere. "If Russell asked me to play in goal, I would give it a go for him," he told the Daily Echo in pre-season.
Southampton's Ryan Manning during the Pre-season match between Eastleigh and Southampton at Silverlake Stadium. (Image: Stuart Martin)
"We have a lot of options with Ryan," Martin responded when asked how important the Irish international will be given the number of players unavailable.
"The same is true with Kyle. He can play in a lot of positions. We have a fair few players that are flexible. Adam Armstrong is the same. It'll be interesting."
Manning is getting more love from supporters since his surprise return to the lineup at Arsenal earlier in the season.
He came in and out of the side during his first year at St Mary's after joining the club on a free transfer from Swansea, following Martin across the bridge.
Supporters voiced concerns over Manning's performances throughout the campaign. The defender later responded that he is a "big boy" and capable of taking criticism.
The 28 year old lost his place in Martin's plans but decided against a move away in the summer. He did not want to throw away his Premier League chance.
Since returning to the fold, Manning has averaged 2.58 shot-creating actions per 90 minutes and ranks third highest in the division for cross accuracy.
He also feels he should have scored against Wolves, but his effort was ruled out by another controversial VAR call.
#WOLSOU – 12’ VAR OVERTURN
Manning’s goal was awarded on-field. The VAR deemed that there was a foul by Fernandes on Semedo in the build-up and recommended an on-field review. The referee overturned the original decision and play restarted with a Wolves free-kick.
— Premier League Match Centre (@PLMatchCentre) November 9, 2024
"I think Ryan played over 35 games in a team that got promoted so I would argue that's a pretty successful first season," Martin continued.
"You have to appreciate sometimes the level of responsibility he takes for the ball and the areas he takes it in. Sometimes that carries a little bit of an element of risk.
"I guess that's what it would be perceived as. I think he's been really good since he's come back into the team. He gives us flexibility. I think he's starting to really believe that he can be at this level.
"A lot of the players are. You can see it in them physically, the body language, the energy they have. They have to keep growing, and he's one of them that is growing at the moment.
"It's great to see because he's a big character in the squad and the players respect him and really love him for what he brings off the pitch as well as on it.
He has to be there all the time for him to stay on the pitch and stay playing. They know the level of challenge now and what they need to be."