Lazio had fought back from 2-0 down to draw level at 2-2, but Davide Ballardini's side now have four points from his first two games in charge and against two of Serie A's top three sides to boot. Lazio slump to a second league defeat in a row, having previously gone 16 games unbeaten in all competitions prior to last weekend.
First half strikes from Marco Borriello and Andrea Bertolacci put the Grifone in cruise control. Sergio Floccari and a Stefano Mauri penalty dragged the Biancocelesti back into it, but Genoa weren't to be denied and have now done the league double over Lazio for the second successive season.
Ballardini opted to rest Ciro Immobile and start Borriello up front on his own with support from Bertolacci. New signings Daniele Portanova and Mattia Cassani were handed debuts while Matuzalem faced his former club. Luca Antonelli sat out a ban along with the injured Antonio Floro Flores, Bosko Jankovic and Juan Manuel Vargas.
Hernanes was out for the visitors after suffering a nasty head injury during Tuesday's Coppa Italia game with Juventus. He joined Brazilian compatriot Hernanes and Antonio Candreva on the sidelines along with suspended central defensive pair Andre Dias and Giuseppe Biava. Miroslav Klose returned for his first Serie A game in three weeks, partnering Floccari in a new look 3-5-2 system.
The confident, new look Genoa took the lead on 16 minutes. A corner wasn't cleared and Borriello was allowed to chest down and fire a thunderous left foot shot from six yards which went in off the crossbar.
The home side doubled their lead six minutes later with a lightning fast counter attack. Michael Ciani was dispossessed in midfield allowing Bertolacci to run at goal and unleash a snapshot which sailed past Federico Marchetti and nestled into the far corner.
Cassani's debut lasted just 25 minutes as he went off injured. Lazio wasted a golden chance to reduce the arrears on the stroke of half time. Cristian Ledesma's free kick from the edge of the area resulted in Alvaro Gonzalez blazing over.
A couple of robust challenges put paid to Klose's afternoon as the German didn't come out for the second half.
Lazio halved the deficit just short of the hour. Floccari controlled a Senad Lulic cross and smashed the ball in off the underside of the bar. Lulic almost equalised, but Thomas Manfredini was on hand to cut out the Bosnian's dangerous pull back.
Matuzalem should have been dismissed for a savage tackle from behind on Cristian Brocchi. The Brazilian didn't even check on his former teammate after being cautioned and Brocchi was stretchered off in pain. New signing Bruno Pereirinha was handed an impromptu debut after his arrival on deadline day from Sporting Lisbon.
Lazio were awarded a penalty when Lorik Cana was wrestled down by Borriello from Mauri's free kick. It was a move straight out of the WWE playbook and Genoa could have no complaints. Mauri stepped up and sent Sebastien Frey the wrong way to draw his side level.
Deep into stoppage time, Marchetti pulled off a superb save to deny Rigoni's point blank header from finding the bottom corner. The substitute had the final say as his second header found the mark from the resulting corner.
Genoa: Frey; Granqvist, Portanova, Manfredini; Cassani, (Ferronetti 25) Kucka, Matuzalem, Rossi, (M.Rigoni 68) Moretti; Bertolacci; (Olivera 74) Borriello
Lazio: Marchetti; Ciani, Cana, Radu; Konko, Gonzalez, Ledesma, (Brocchi 64) (Pereirinha 71) Mauri, Lulic; Floccari, Klose (Kozak 46)
Goals: Borriello 16 (G) Bertolacci 22 (G) Floccari 58 (L) Mauri 82 pen (L) Rigoni 90+5 (G)