The pair have become the latest names on a long injury list having been forced off during Wednesday’s defeat by Aston Villa.
Wanyama has a hairline fracture in his lower leg, while Clyne has suffered a groin injury. They join Artur Boruc (hand), Morgan Schneiderlin (groin), Kelvin Davis (gluteus), Guly do Prado (knee) and Danny Fox (hamstring) in the treatment room.
José Fonte will be assessed after being restricted to a substitute’s role in midweek, while Gastón Ramírez looks set to be available after illness.
But, while admitting the situation is far from ideal, Pochettino insists the squad’s belief levels will remain high as Saints look to arrest a run of three consecutive defeats against a talented City side.
“Of course, injuries always change your plans and your outlook,” the manager told Saints Player
“They will have a negative impact on you, but we need to keep on working and believing in the way we have done.
“I enjoy everything in football. Obviously, I’d prefer to enjoy the positive moments because no-one wants to go through negative times, but I need to be fully-focused and to relish these moments when they come around.
“Manchester City have some great players so we’ll be facing a great side – we all know that,” Mauricio continued. “It’s a very tough test.
“When we don’t have possession, we need to pressure them. They have very good players who are able to impose themselves very well, so we need to be able to neutralise that to cut the supply to dangerous players.”