The centre-back was substituted shortly before half-time in England's 1-1 friendly draw against Italy on Tuesday.
And it remains to be seen if Smalling, who drew praise for fine performances in the wins over Tottenham and rivals Liverpool before the international break, will be fit enough to feature in this weekend's contest at Old Trafford.
"Smalling is ill - I don't know if he is available," manager Louis van Gaal said. "Yesterday [Thursday] he was at the club at the medical department doing recovery and so on.
"Today he is not feeling well. It shall be difficult for him."
Van Gaal also stated that fellow Dutchman Robin van Persie is not yet ready to return to action.
The striker has been absent for over a month with an ankle injury and, although he has stepped up his recovery, Saturday's match will come too soon.
Full-back Luke Shaw is closer to a comeback than Van Persie after pulling out of the England squad with a hamstring problem.
"Van Persie is still injured," Van Gaal added. "We have a process. He has to go to the final football coach before he comes into my group and he is not there yet. He is still not in my group. But Luke Shaw is in my group."
Van Gaal reiterated that his focus for this season is to finish in the top four.
United's wins over Tottenham and Liverpool strengthened their grasp on fourth, but Van Gaal believes the race for UEFA Champions League places remains a "rat race" with his team facing upcoming games against Chelsea, Manchester City and Arsenal.
"The top four is still a rat race," he said. "I said when we had 13 points from 11 games and we were getting a lot of criticism that we would see at the end of the season. We will still see at the end of the season. We still have the top three to play.
"Can we still win the title? Mathematically, we can still do it."
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