Ricardo Horta's first senior goal - in the 74th minute - proved enough to separate the teams at Estadio de Bonfim and lift Setubal into ninth position.
Academica's frustration was compounded by the late dismissal of Rafik Halliche, who picked up a straight red card in stoppage time at the end of the second half.
After a poor start to the season, Jose Couceiro's Setubal are now unbeaten in eight games across all competitions and have won three of their last four league games.
Academica, who slip to 12th, had claimed successive wins heading into Monday's game - including a famous home triumph over Porto last time out.
Yet they were brought back down to earth as Setubal continued their recent rise.
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