Smalling out for 10 weeks after surgery
The 22-year-old, who did not travel on the club's pre-season tour to South Africa, missed the end of last season, Euro 2012 and an Olympic call-up with a groin injury.
He was expected to be ready for the new Premier League campaign but injured his toe in training on Wednesday and the surgery on the broken metatarsal means he will miss the start of the season.
"He got an injury on the Wednesday and, straight away, we decided to have the operation so he's out," Ferguson told the club's television channel 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 Nemanja Vidic, Jonny Evans, Rio Ferdinand and Phil Jones for a centre-back role.
United captain Vidic should be fit to start the season after a cruciate knee ligament operation but Evans is a doubt for the league opener at Everton on August 20 with an ankle problem.