The versatile defender had his fair share of injuries throughout last season, and was unavailable for selection at Euro 2012.
So United are used to dealing without him, but how will it affect them going forward?
Well he is not the first centre-back with fitness concerns. Northern Irishman Jonny Evans did not go on tour and is yet to return to full training after a foot operation.
Evans was United's first choice partner for Rio Ferdinand last season, but the good news is captain Nemanja Vidic has returned.
As far as first team selection is concerned, Ferdinand and Vidic should renew their partnership when the season kicks off, but it will leave Phil Jones as the only real cover in the centre.
Ferguson will hope Rio Ferdinand's fitness keeps up, which it did for most of last season, but it has caused him problems previously.
Jones will be a key utility man, with Rafael da Silva first choice right-back, he will be the cover there in case of the Brazilian experiencing any troubles. Smalling would have been cover too but will now no longer be available.
Rafael is on Olympic duty with Brazil, and United will hope he comes back in tip top condition and raring to go.
With a tough away fixture to Everton as their opening fixture, United may just go with Jones in the starting line-up and Rafael easing in way back in from the bench.
The issue with Jones being needed as cover in central defence and right-back, is that injuries to two of either Ferdinand, Vidic, and Rafael, would leave United stretched to the limit.
Remember United have loaned out Fabio da Silva, who can also play right-back, but his absence also leaves them with no experienced cover at left-back.
At a push Jonny Evans could fill in either full-back position, but again it appears he may not make the start of the season.
United took a number of youngsters on their pre-season tour in South Africa, and Ferguson is believed to have been assessing them not only long-term, but also in the short-term should they be needed.
Robbie Brady is being looked at for left-back cover, which young Belgian defender Marnick Vermijl came on at right-back against Ajax Cape Town and provided the cross for which Bebe netted United's equaliser.
In the absence of Fabio, Evans, and now Smalling, Vermijl could find himself as a third choice right-back for the club.
United elected not to go in for Crystal Palace's Nathaniel Clyne, and at left-back they have been linked with Leighton Baines, but as time goes on that deal is appearing increasingly unlikely.
Importantly Chris Smalling's absence re-inforces Phil Jones' importance in defence. We had speculated whether Jones would be used increasingly as a midfielder, to replace the ill Darren Fletcher.
At the start of the season at least, this now appears unlikely, and may add to the list of reasons for Sir Alex Ferguson to add new faces to the club's midfield.
So while not affecting Ferguson's first choice selection, Smalling's injury removes a layer of security should any of his first choices suffer injuries of their own.
Any more, and United's start to the season could lurch from undergoing minor disruption to major, while the silver lining could be Ferguson dipping into the transfer market.
Are you concerned at the way United are picking up injuries or do you think they will be fine?
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