James Hunt's second-half strike ensured a shock win for Grimsby that dents MK Dons' automatic promotion bid.
Tom Newey found Danny Boshell unmarked and he unleashed a ferocious volley inside the post and Hunt doubled their with another fine strike.
Paul Bolland was denied a third before Keith Andrews pulled a goal back when he swivelled 10 yards and fired home.
Grimsby's Peter Till hit the crossbar while Izale McLeod blazed over a great chance to equalise for the Dons.
Milton Keynes Dons: Harper, Edds, Diallo, O'Hanlon, Lewington, McGovern (Stirling 46), Andrews, Blizzard (Knight 46), Dyer (Jarrett 68), Platt, McLeod.
Subs Not Used: Baines, Hayes.
Goals: Andrews 71.
Grimsby: Barnes, McDermott, Fenton (Grand 74), Whittle, Newey, Bore (Till 56), Bolland, Boshell (Bennett 88), Hunt, Toner, North.
Subs Not Used: Murray, Jones.
Booked: McDermott, North.
Goals: Boshell 32, Hunt 53.
Ref: A Marriner (W Midlands).