The striker heads back to the San Paolo, where he spent three years prior to joining Siena in 2008, in a deal which sees him initially arrive on loan for the next six months
The 31-year-old becomes the second Partenopei arrival in a matter of days, following in the footsteps of Colombian wing-back Pablo Armero earlier in the week.
He will initially arrive at the San Paolo on a temporary basis for the next six months, but the southern Italian club have the option to make his stay permanent in the summer.
Walter Mazzarri's side are understood to have beaten Torino and Palermo to Calaio's signature, and his arrival is expected to speed up Eduardo Vargas' return to South America.
The Sicily-born hitman originally joined Napoli in the 2004-2005 season and went onto score 44 goals in 128 appearances before falling out of favour and joining Siena three years later.
However, he regained his form at the Artemio Franchi, netting a further 50 times during his spell in Tuscany, and will now likely serve as Edinson Cavani's deputy.