Schalke coach Ralf Rangnick rested several players in their 1-0 home defeat to Kaiserslautern on Saturday.
"We will have a different starting team against United," said Rangnick, who took over from sacked Felix Magath a month ago.
"If I had chosen the same team on Tuesday that I did today I don't think we would have a big chance to win against Manchester," he added.
Peruvian Jefferson Farfan, who missed the quarter-final second leg against Inter, will be back in midfield while defenders Benedikt Hoewedes, Atsuto Uchida and Hans Sarpei should also return.
Midfielder Jose Jurado, who came on as a substitute on Saturday, is also expected to start in Schalke's maiden Champions League semi-final appearance.
Schalke, despite being 10th in the Bundesliga, still have two titles to fight for this season with the Champions League and their German Cup final against second division Duisburg in May.
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