The 31-year-old playmaker has penned a three-year contract with the Rossoblu.
It was expected that Santana would be on the move this summer after falling out of favour at Napoli.
He spent the 2012/13 campaign on loan at Torino and remained on the fringes of the fold after returning to Naples.
Santana is delighted to have secured a permanent switch elsewhere and is looking forward to working under new Genoa boss Fabio Liverani - a man he played alongside during their days together at Fiorentina.
He told Pianetagenoa1893.net: "I cannot wait to get started.
"I know Liverani very well and he convinced me to choose Genoa during a phone conversation."