After winning an architecture contest in the Accademia Albertina, he moved to Rome in 1828, where he studied deep descriptive geometry.

He elaborated a functional ideal of architecture, which inspired him with an ambitious plan for the renovation of Turin's historical centre.

He was also a deputy in the Kingdom of Sardinia's Parliament, and a member of Turin's communal council and of the Province of Novara's one.

In this period he designed numerous works: several residences, the communal seta and the Sanctuary of Boca (whose cupola was never completed due to crumbling risks), a villa at Romagnano Sesia, the Orphans' Hospice in Alessandria, the regulation plans of Ferrara and Novara, the church of San Clement and the Asilo de Medici in Bellinzago Novarese.

Antonelli's most famous work is the Mole Antonelliana, the symbol of Turin, named after him and begun in 1863 as a Jewish synagogue.