Former Cardiff City boss Neil Warnock proved the final straw for Bluebirds boss Mick McCarthy, who stepped down following this eighth straight defeat.
Cardiff are now on their worst-ever run and have been beaten in their past six home games, also a new club record.
Middlesbrough took a deserved lead when Andraz Sporar scored from the penalty spot after Mark McGuinness' handball.
Martin Payero made the result safe with a smart 73rd-minute finish after Aden Flint hit the crossbar for Cardiff.
The Bluebirds did improve after half-time but there can be no denying they were second best in a game where their supporters again chanted against their own manager, with cries of "you're getting sacked in the morning" ringing out at Cardiff City Stadium.