Alberto Gilardino and Ioannis Fetfatzidis scored the goals for Gianpiero Gasperini's men, who can now look forward to another season in the top flight having put 39 points in the bank, only three less than their guests.
For Lazio, it was an evening to forget as they also lost Cristian Ledesma to a red card late on.
Genoa could have been in front within a minute, but Stefano Sturaro volleyed wide.
Marco Motta's header was saved by Etrit Berisha as Genoa mounted an early assault on the Lazio goal.
Lazio responded and Stefano Mauri sent a shot over the crossbar before, back at the other end, Andrea Bertolacci wasted too much time from Gilardino's pass, and another chance went begging.
Former Lazio goalkeeper Albano Bizzarri came to Genoa's rescue 10 minutes before half-time when he saved Balde Keita's deflected effort, and the half ended with Gilardino shooting straight at Berisha.
Lazio saw their strong appeals for a penalty waved away by the referee on the hour mark when Mauri went down under the challenge of Riccardo Centurion, and five minutes later, Gilardino put the hosts in front.
Giuseppe Sculli, another former Lazio player, timed his pass to perfection to set up Gilardino, who needed just two touches to beat Berisha.
The Italy striker nearly made it two within minutes, but Berisha made an excellent reaction save to deny him.
A former Genoa player now on the Lazio books, Abdoulay Konko was then at fault as Genoa doubled their lead and put the game beyond Lazio in the 83rd minute.
He played Fetfatzidis onside from Cabral's pass, and the Greek midfielder picked his spot in the far corner of Berisha's goal.
Things went from bad to worse for Lazio, who lost Ledesma to a needless red card with just a few minutes to go.
After earning a first yellow card for protesting, the Argentinian continued to protest, prompting the referee to extract his yellow card once again, and show a red to compound Lazio's woes.