The defender missed out on a possible place in the Great Britain Olympics squad and the DHL tour but Sir Alex Ferguson initially expected him to be ready for the start of the season.
However, the surgery to fix the toe problem means he will now miss the early part of the campaign.
"He got an injury on the Wednesday and, straight away, we decided to have the operation so he's out," the manager revealed to MUTV. "It's difficult to say with a metatarsal but it could be 10 weeks.
"He's not carrying any luck, the kid, but he's young and we've done the right thing in getting it done immediately and getting him back on the road as quickly as we can."
Smalling is expected to compete with Jonny Evans, Rio Ferdinand and Phil Jones for a centre-back slot, along with Nemanja Vidic as soon as the skipper returns to fitness. Evans is already a doubt for the Barclays Premier League opener at Everton while Scott Wootton has played both tour games in the middle alongside Ferdinand.