The Scotland international suffered a calf injury during training earlier this week.
Fletcher netted 12 times last season in helping Wolves survive in the Premier League and is their leading marksman with three goals during the current campaign.
Wolves boss Mick McCarthy confirmed: "Steven Fletcher has hurt his calf and is a real doubt. In fact, I would say he is out. It is sad but that's the way it is."
With Wolves' other experienced striker Sylvan Ebanks-Blake not match-fit after his knee problem, McCarthy could be forced to alter his formation from 4-4-2.
But deputy left-back George Elokobi's ankle injury means Stephen Ward is unlikely to be pushed forward into the attacking role he has been employed in on several occasions in a 4-4-1-1 system.
Source: Team Talk
Source: Team Talk