Born in Florence to a family that had originated at Montevarchi, he frequented the neoplatonic academy that Bernardo Rucellai organized in his garden, the Orti Oricellari; there, in spite of the fact that Rucellai was married to the elder sister of Lorenzo de' Medici, republican ideals circulated, in the context of revived classical culture, that culminated in a plot in 1513 to subvert Medici rule in Florence. At Pisa, Varchi studied to become a notary.

With his return to Florence, he fought in the defense of the temporarily revived Republic of Florence, during the siege by the Medicean and imperialists in 1530, and was exiled after the surrender of the city; he spent time at Padua (1537), where he was a protégé of the émigré Piero Strozzi and at Bologna (1540). In 1536 he took part in Strozzi's unsuccessful expedition against Medicean rule, but seven years later Varchi was called back to Florence by Cosimo I who, who gave him a pension and commissioned him to write a history of the city. His Storia fiorentina