The German picked up the injury during the second half of City's 2-0 victory over Sunderland last weekend and may now require surgery.
Hughes admits an operation cannot be ruled out but is hoping Huth could be back in contention for a starting role following a period of treatment and rest.
Speaking ahead of Stoke's trip to Everton on Saturday, Hughes said: "Robert didn't complete the game last weekend and hasn't been able to train at all this week, so he's not going to be available for the game.
"He's got a little bit of an issue that we're going to try and manage initially. Obviously, if that doesn't work then he will probably need the knee seeing to.
"We're hopeful that with the work he's doing with the medical team we'll be able to settle it down and he'll be able to play again."
And Hughes must take on Roberto Martinez's side without striker Marko Arnautovic who is struggling with a hamstring problem.
"Marko pulled up with a hamstring strain that will keep him out for a couple of weeks," he said.
"It is a disappointment, but we are hopeful of having him back available soon."