Natoli was born in Messina, in Sicily, on 9 June 1815, the son of Giacomo Natoli and Emanuela Cianciolo. He studied oratory and philosophy at the Accademia Carolina of Messina, and then studied law at the University of Palermo, where he graduated at the age of 22. From 1843 he taught at the University of Messina. He was offered a post as a judge, but declined it, not wishing to serve the Bourbon king. Natoli took part in the Sicilian Revolution of 1848, and as a result fled Sicily for Turin, where he spent eleven years in exile. In 1860 he was involved in organising Garibaldi's venture against Sicily, and embarked with the second wave of ships. Under the dictatorship of Garibaldi he was briefly minister for agriculture, and acting minister for foreign affairs.