The loser of the match will be in serious danger of getting relegated from League One - with Mk Dons currently sittign 22nd in the table, two points below Rotherham.
However, sat between them is Hartlepool United who, as long as Rotherham lose, could secure their own survival with a win at home to Port Vale.
MK Dons boss Danny Wilson, whose side clinched survival in the last minute of the final day last year, insists his players must focus solely on defeating Rotherham though.
"We have to be mindful of the scores elsewhere, but as far as the players are concerned they have to go to Rotherham next win the game," he said.
"End of story. There's no in-betweens. And from Rotherham's point of view, they'll be wanting to win. It will not be an easy game.
"And if we'd have taken things back six or seven games when we were in a real, real perilous situation, we wouldn't have given ourselves a cat in hell's chance of getting to the last game of the season with a chance to stay up.
"But we have, and if we go to Rotherham and win, and if somebody else has a decent result in favour of us, then we stay up.
"But first and foremost we have to go to that game and get the maximum points, and see what happens after that.
"But we saw last year, when you're down and out, you know there are twists of fate, and let's hope we can turn it in our favour again."