Marco Borriello scored two and set up another for a buoyant Grifone, whose victory over the bottom-placed side never looked in any doubt.
Andrea Bertolacci and Antonio Floro Flores were also on target for Davide Ballardini's side with former Genoa favourite Giuseppe Sculli scoring a consolation for Pescara, who become the first side to be relegated from Serie A this season with three games of the season to go.
Pescara almost silenced the home fans in the 14th minute when Sculli's cross was headed inches over by Ferdinando Sforzini, but they were soon celebrating when Floro Flores put them in front.
Matuzalem's free-kick was laid off by Thomas Manfredini for the former Udinese forward, who headed past Mattia Perin.
Genoa did not sit on their lead in the slightest, though, and they searched for a second, which they got less than 10 minutes later.
Borriello received a long ball on his chest and, without hesitation, turned and sent an unstoppable shot in off the inside of the post in the 29th minute.
Floro Flores almost made it three moments later when he sent a shot just wide of the post.
It looked like Genoa were going to run away with it, but their former forward Sculli had other ideas as he brought Pescara back into the game 10 minutes before the break.
He met Zanon's cross from the right to place an unstoppable header past Sebastien Frey, although his celebrations were understandably subdued.
The home fans broke out in cheer again 10 minutes into the second half when Borriello unleashed a powerful shot which flashed past Perin to restore Genoa's two-goal advantage.
And the game was over as a contest in the 69th minute when Bertolacci tucked the ball in to the empty goal after Borriello made enough of a nuisance of himself to prevent Perin from making a clean catch.