St Johnstone expect to be without defender Tam Scobbie for three months and fear striker Steven MacLean could also be absent long term.
Manager Tommy Wright explained the extent of their knee injuries after Saturday's 1-0 defeat by Dundee.
MacLean, 32, who missed four months of last season through injury, will have an exploratory operation on Tuesday.
"Speaking to the medical team today, it will be three months if Tam Scobbie needs an operation," said Wright.
"It looks like he will probably need an operation to resolve the problem."
Both players have featured in seven of St Johnstone's nine outings this season before missing Dundee's visit, with MacLean scoring three times.
"Steven's got an operation on Tuesday," Wright told BBC Scotland. "Hopefully that'll just be a clean up and it will be a matter of weeks.
"But there is a concern that it is the same knee trouble as last year and the consultant won't know until he goes in and has a look."
Wright, whose side were seeking a third straight victory, was disappointed to lose at home to Gary Harkins' first-half strike.
However, he remained satisfied with the Perth side's start to the season.
"It is a good start to the season because we've got nine points - it took us nine games last season to get nine points," he said.
"We're disappointed today, but these players will bounce back.
"That's what they have always done week-in, week-out over the last few seasons."
Wright admitted his side had failed to cope sufficiently win an in-form Dundee side, who have not lost in 10 games stretching into last season.
"We came awake a wee bit after we conceded a goal and we knew about their set plays, so to concede a goal from one was disappointing," he said.
"Because, for all their possession, they didn't really create anything until that moment.
"Once the goal went in, they had a lot of good opportunities, particularly down the right-hand side, but our final ball and our crossing was poor and we didn't make enough of those opportunities.
"In the second half, we basically huffed and puffed and didn't do enough to get into the game.
"In spells of the game we did okay, but you have to give the opposition a bit of credit - Dundee played particularly well."