Both sides have struggled so far this season, with Palermo just one point clear of Frosinone and the relegation zone, but it was the home side who came out firing as Uros Djurdjevic hit the post inside the first minute of the game.
Buoyed by that immediate near miss, it took them a little under five minutes to break the deadlock, as Oscar Hiljemark's free kick found Edoardo Goldaniga and the defender turned the ball home from point-blank range.
All of the early play belonged to Palermo and they hit the woodwork for a second time within the first 11 minutes when Hiljemark cracked the post after letting fly from 30 yards.
They deservedly doubled their lead with only 17 minutes on the clock when Franco Vazquez slotted home from 12 yards after he was found by Djurdjevic's neat through-ball, and the striker could have added a third minutes later when he shot narrowly wide.
Frosinone began to work their way into the game as the first half wore on and after Daniel Ciofani had gone close, they halved the deficit through Paolo Sammarco, but their task was made more difficult when Leonardo Blanchard was sent off for picking up two yellow cards in the space of a minute.
Ciofani missed another chance to reduce the deficit just before the hour mark, and less than a minute later he and Frosinone were made to pay for their profligacy when Aleksandar Trajkovski cut inside and bent home a fine effort from the left side of the box to restore Palermo's two-goal advantage.
Alberto Gilardino added some gloss to the scoreline when he nodded in a late fourth after Ivaylo Chochev's effort had been saved as Palermo won for the first time in five matches to pull four points clearof the bottom three.