Gracia Mendes was born in Portugal in 1510. Her Christian name was Beatrice de Luna. She was a secret Jew. In 1528 she married Francisco Mendes, also a secret Jew. He and his brother had built up a fortune by starting with precious stones and branching out into banking. He died, and Beatrice joined her brother-in-law in Flanders. She began helping secret Jews who were desperately fleeing from the Portuguese Inquisition.

In 1543 her brother-in-law died, and Beatrice fled Flanders and went to Venice. Her sister denounced her as a Judaizer, but Beatrice escaped the clutches of the Inquisition. She settled in Ferrara, declared herself a Jew, and took on her name Gracia Nasi. She continued to help a huge number of secret Jews. She became the patroness of scholars.

In 1558 she arranged with the Turkish sultan to buy the city of Tiberias in Israel with the intention of making it an independent Jewish city-state with her son-in-law the head. The plan almost succeeded. Work began on renovating Tiberias, but, because of conflicts between Constantinople and Italy, the final deal fell through.