Odemwingie was carried off on a stretcher during the Potters' Barclays Premier League victory at champions Manchester City last Saturday.
Hughes initially expressed hope the problem was not serious but now it has emerged the 33-year-old Nigeria international will need an operation.
As yet no timescale has been put on his recovery but the club have not included Odemwingie in their 25-man Premier League squad, meaning he cannot be registered to play until January at the earliest.
Hughes told the club's website, www.stokecityfc.com: "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."
Odemwingie only entered the action as a half-time substitute at the Etihad Stadium and almost set up a second goal for match-winner Mame Biram Diouf.
But he was injured in the process and was himself substituted after 65 minutes.
Odemwingie 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.
Source : PA
Source: PA