Liverpool defender Wisdom picked up a shoulder injury while on club duty, while 19-year-old Powell has been suffering with illness.
Friday’s match at Carrow Road is the first of a two-legged play-off for a place in the European Championships next year and manager Stuart Pearce is not prepared to force either player to play too early.
“Andre went over on his shoulder playing for his club and it was something that just didn’t ease up at all,” Pearce told the Football Association’s official website.
“We got him on the training pitch on Wednesday but we just felt that it wasn’t easing up, so he’s gone back to Liverpool.
“Nick has had a bug since day one. We tried to give him every chance to be fit and shake it off but we’ve had to send him back to his club, too. Hopefully he’ll be back with us next month.”
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“We’ve pulled a team out of the hat who are unbeaten in qualifying,” he said.
“Defensively they are very strong and, similar to us, they have had a lot of players who have gone into the senior squad and come back down again.
“It’s going to be a tough game and I’m sure it won’t be won or lost on Friday evening; it’ll go over the two legs and will be very tight. We expect the odd goal will separate the two of us.
“They are a good side and we are under no illusions about that. But we’re a good team, too, with some very good players, so I think it will be a great advert for Under-21s football.
“We’ll be going out to try and win both games, and I’m sure Serbia will be thinking the same. They’ll want to keep it tight and try to get us back to their place and win the match from there.
“From our point of view, we’ll endeavour to get a result on Friday and I don’t see it changing when we go on the road either.”