The Black Cats confirmed on Wednesday that skipper Lee Cattermole will not play again this season after undergoing knee surgery, while leading scorer Steven Fletcher will also sit out the remainder if the campaign with ankle ligament damage.
O'Neill said: "The injury to Cattermole, really we have foreseen that one for some time, and the injury to Fletcher is a blow to us, but we have got to get on with it."
The loss of two key men could hardly have come at a worse time for Sunderland, who head into the final eight games of the season without a win in seven outings and sitting just four points clear of the drop zone ahead of Saturday's home clash with champions-elect Manchester United.
Asked if it was tough to take, O'Neill said: "Of course, but it's the nature of the game and you get these things during the course of a season.
"What you have to do is be as prepared as possible for that eventuality and deal with it."
Fletcher was hurt on international duty with Scotland, and club-mate David Vaughan returned early from the Wales camp with a groin problem.
Vaughan, along with Stephane Sessegnon, who did not meet up with Benin because of a minor injury, is being assessed, while defender Carlos Cuellar remains a doubt for the weekend with an ankle injury.