Down got their second league win of the season to move off the bottom of Division One of the National League.
Mayo were a point up when they had Aidan O'Shea sent-off in the eighth minute for striking Daniel Hughes.
Down got their goal when Conor Laverty found Conor McGinn who flicked the ball past Mayo goalkeeper Robert Hennelly.
McGinn, Aidan Carr (4) and Ambrose Rodgers reeled off unanswered points as Down stormed into a 1-7 to 0-6 lead and they went on to seal the win.
Scores by Conor Mortimer, Alan Dillion and Alan Freeman brought unbeaten Mayo to within two at one stage.
But Benny Coulter, on as a second-half substitute, scored three points for the Mourne county and another by Danny Hughes increased the victory margin.
Carr ended Down's top scorer with five points while Mortimer, closing in on Mayo's scoring record, got six, all from frees.
After back-to-back defeats, this win at Castlebar will ease the relegation worries of Down boss James McCartan.
They have four points from four matches and are at home to All-Ireland champions Dublin next Sunday.