Stephen O'Neill and the McMahon brothers - Joe and Justin - have been ruled out of Tyrone's first two matches in the National Football League.
The injured trio will miss the league opener against Derry on 1 February, as well as the clash with beaten All-Ireland finalists Mayo a week later.
Former Footballer of the Year O'Neill is troubled by a long-standing knee problem, as well as an ankle injury picked up in last year's All-Ireland semi-final defeat by Mayo.
Versatile Joe McMahon is recovering from a groin injury problem, while his younger brother, defender Justin, continues to struggle with hamstring trouble.
But manager Mickey Harte hopes to have Sean and Colm Cavanagh back for the trip to Celtic Park.
"The Cavanagh brothers are closer than the McMahon brothers. Of the players who are out at the minute, they would be the two who are closest to getting back into the frame at this stage," said Harte.
"Stevie would not be happy with his injury situation, so he definitely won't be back for the start of the league."
Others, such as Conor Gormley, who had a long season with Carrickmore who reached the league and championship finals, have not yet returned to the Tyrone camp.
"I have not spoken to Conor yet about when he will be ready to come back again, and I have to chat with a few players.
"After the first two games, we will probably be in a better position to decide where we stand with players who are returning from injury."
After facing Derry and Mayo, the Red Hands have a three-week break ahead of their third NFL game away to Mayo on 2 March.
"It all depends on how ready they are. Some of them are further ahead than others, and we have to assess that after next week, to see who is ready," added manager Harte.
"Some of them may be returning to training this week, and when the McKenna Cup is over we will have a better idea of who is nearly ready to come back in to the frame, and who is a bit further down the road, and that will influence our decisions."
Harte must now decide whether to stick with the squad, largely made up of fringe players, who have featured in the Dr McKenna Cup for the opening league tie against Derry, or recall more established figures despite their lack of game time.
Tyrone reached the Division One final last season, losing narrowly to Dublin. Harte plans to challenge for the title once again, but expects an even tougher challenge in 2014.
"There are no easy games in Division One. It is a bit of a myth, people thinking there are easy games. There are just hard and harder."