Smalling had been training at United's Carrington HQ after recovering from a thigh injury that ended his hopes of appearing at Euro 2012.
However, it has now been confirmed the 22-year-old has suffered a new setback.
United manager Sir Alex Ferguson told MUTV: "He got an injury on the Wednesday and, straight away, we decided to have the operation, so he's out.
"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."