Cattermole has managed just ten Premier League games so far this season, thanks to injuries to both knees.
With eight games of the season left, Sunderland are just four points off the drop zone and had hoped Cattermole could make a return sooner rather than later.
But O'Neill admits he may have to do without his influential skipper and told the Sunderland Echo: "Lee has a few more days to go after having had the injection.
"The specialist told him not to do a great deal and while he is obviously working with the physiotherapist, he is not doing anything that will risk damaging his knee.
"We hope for the best but, to me, if he comes back this season, then that would be a bonus - and an unexpected bonus.
"We may have to cope without him and even if he does successfully come back from the injury, he will still be nowhere near match fit."
O'Neill admits they have struggled in Cattermole's absence, adding: "We have had to do without him pretty much all season. He has definitely been a loss to us, no question about that.
"We have missed that drive, the things that he would give us, but we have had to make do without it.
"We've had different combinations in midfield, we've had to play midfield players at full-back - all those type of things which eventually get lost in the mix.
"It has been a tough old season. It has been tough since the very first day down at the Emirates Stadium and that's just the way it has been.
"But I think because we've been uncomfortably placed, the players are used to that, and should be able to rise to the occasion in these key games ahead."