The loss was the Genoa outfit's fourth in a row and saw Cagliari win their third successive match under new coach Ivo Pulga.
The hosts started the game the brighter of the two teams, with Daniele Gastaldello heading just wide.
However, things changed at the start of the second half, as Cagliari surged ahead.
Thiago Ribeiro whipped in a cross from the right that Daniele Dessena dived in between two Sampdoria defenders to score.
Gastaldello should have equalised for Sampdoria when he found himself with the ball in front of an open goal, but he failed to keep his header on target.
Gianni Munari thought that he had scored for Samp when he nodded in a free kick at the back post, but his effort was ruled out for an offside infringement.
Cagliari could have doubled their advantage in the final minutes of the match, but Tommaso Berni made a flying save from a long-distance shot.