The Italian international damaged ankle ligaments during Saturday's friendly with Hull City, after falling awkwardly.
The full extent of the injury is not yet known, as the player has had his ankle placed in plaster, but Boro are hoping he will be back in training within a month.
"Unfortunately, Massimo will certainly miss the start of the season, which is a big blow to us because he was looking so well in pre-season," said McClaren.
"But what we've got to do now is concentrate on getting the lad right and back on the pitch as quickly as possible."
Maccarone is just the latest blow for McClaren, who is already without David Murphy (foot), Ugo Ehiogu (knee) and Franck Queudrue (suspended) for the start of the season.
George Boateng (ankle) and Michael Ricketts (Achilles) are also not certain to make the opening game at Fulham, leaving the Boro boss with a seriously depleted squad before a ball has been kicked.
McClaren is hoping to bring in at least two new faces before the start of the season, one of whom could very well be left back Alan Wright who is still on trial with the club and hoping to win a permanent deal.
