Matt Derbyshire struck in the first minute before Leon Best scored from the penalty spot after goalkeeper Cody Cropper brought down Richard Wood.
The visitors confirmed their dominance through Kirk Broadfoot's header and Richard Smallwood's neat finish.
Rotherham, 21st place in the table, moved nine points clear of MK Dons, who remain third bottom.
The atmosphere inside Stadium MK was tense before kick-off, but almost immediately the Rotherham fans were celebrating as Derbyshire opened the scoring.
Best then slammed home from the spot, and it was no surprise when Broadfoot and Smallwood put the game beyond MK Dons just after the break.
Ex-Miller Alex Revell almost pulled one back for the hosts, but Rotherham easily held on.
Despite languishing in the relegation zone in mid-February, Neil Warnock, Rotherham's third manager of the season, has turned his side's fortunes around, winning six of his 11 league games in charge.
MK Dons manager Karl Robinson:
"It's extremely difficult and very hard and the odds are stacked against us. We only have ourselves to blame.
"You get that tag of losing football matches and it's so hard to shift. You have to find it from somewhere to cope with the demands of this level.
"We were the better team in between the two boxes by far, (but) we are not as good as other teams in the boxes, it's as simple as that.
"I don't think it's fair to boo me individually, I don't agree with that. Collectively we have to take responsibility. "
Rotherham manager Neil Warnock:
"It was an important game but I thought it was a comprehensive victory.
"We started well with the goal and we couldn't have got off to a better start. We missed a few chances in the second half, but we can't get too greedy.
"It just goes to show what you can do with a good group who want to listen.
"I think they are amazing themselves with the ability they have and what they can do with the ball. It's a great time and we are enjoying ourselves."
Rotherham took a huge step towards retaining their Championship status by thrashing relegation rivals MK Dons.