This essay focuses on the Vespasiano Gonzaga Colonna (1531–1591), a remarkable example of long-term life following cranial trepanation during the Renaissance. Gonzaga suffered from syphilis and frequent migraines; therefore, in 1578, his court surgeon used a scraping procedure to perform cranial trepanation. The right parietal bone had obvious indications of healing, and osteological data from his tomb validated the surgery. One of the longest reported survivors following cranial trepanation in the Italian archaeological record, Gonzaga, lived for 13 years after the treatment. This instance adds to the historical understanding of trepanation as one of the earliest neurosurgical procedures, and demonstrates the high degree of surgical expertise attained in early modern noble courts.