The Nigerian striker was carried off during last Saturday's 1-0 win at Manchester City, but Hughes initially hoped he had avoided serious injury.
Unfortunately his worst fears have been confirmed and Odemwingie was left off the club's 25-man squad list, meaning he cannot be registered to play until January at the earliest.
Hughes told the club's website: "He's going to have some kind of procedure but the medical staff are waiting for the knee to settle down.
"He's going to have to wait a couple of weeks before it's actually done but once the operation is done we know he will work extremely hard to get back.
"It's a significant injury and unfortunately it's a long-term one, but Peter has a great attitude to work and life in general - he's always got a smile on his face - and he's going to need those qualities. It will be a long road back but we wish him well."
The news comes as a blow to Odemwingie, who appeared to have settled well at Stoke following his move to the Britannia Stadium last January.
His three-year spell at West Brom ended in acrimony a year ago and a subsequent switch to Cardiff failed to reignite his career.