The defender injured his calf during Saturday's 1-1 draw with Blackburn and boss Paul Warne does not think he will be fit enough for Tuesday's game at Luton or Saturday's curtain closer against Cardiff.
The Millers need to take a minimum of three points to stay up, with six ensuring they will definitely survive the drop no matter what happens between Derby and Sheffield Wednesday on the final day.
But MacDonald will not be a part of their survival bid.
Boss Warne said: “In fairness, Angus has been one of those players who is dogging in there and has been struggling with his calves and did not train much last week and we have had to patch him up and get him out for games.
“I think his calf has gone. Prior to the goal, I said, ‘Are you all right’ and he went, ‘Yeah, yeah’.
“But I thought he was not moving very well. There was a throw-in near the dug-out side, Blackburn side, and he came running over and I thought he was not moving very well.
“I have spoken to the physios, but I presume he would be unavailable for the next games.”
Goalkeeper Viktor Johansson is in contention for the crunch game at Kenilworth Road as he recovers from a facial injury.
Johansson has missed the last two games due to concussion protocols, with Warne not prepared to risk him against Rovers.
“He passed all his protocols, which is pretty tough and strict,” he said.
“He only trained yesterday for the first time. I thought Jam did well, first and foremost.
“But also with a goalkeeper who has been smashed in the face and has been concussed, if a ball came in, in the first minute, today, how we have feel about coming to get it. He is a warrior, by the way. Also and it is on me, what would if he got hit again.
“I just thought Saturday was too soon and Tuesday is a different game and I will look at it for the right reasons.”