The in-form England international missed the midweek Carabao Cup loss at Southampton with a fitness issue and has not recovered in time to feature this weekend.
"He is not ready," said Guardiola at a press conference.
City midfielder Ilkay Gundogan suggested City had been lacking hunger after their unexpected defeat to the Premier League's bottom side at St Mary's on Wednesday.
Guardiola admits this could be a natural consequence of the team's success of recent years.
He said: "What happened didn't surprise me. We tried to avoid it and hopefully it is not going to happen again, but it happened because we won four Premier Leagues in five years.
"After back-to-back two times, this can happen. We were not ready to go there. I was concerned it could happen and unfortunately it did. I don't know if will happen again, but I am not concerned."
City thrashed their neighbours 6-3 when the sides last met in October, but United have lost just one of 18 games since.
Guardiola said of United: "The improvement is clear - not just in results.
"I have the feeling every time (we play them) at Old Trafford or the Etihad it's a difficult game.
"They are always attractive games. There are a lot of quality players on both sides. It will be a good game."