Rabbi Yitzchak ben Yosef Karo was born in Toledo in 1458. A student of Rabbi Yitzchak Canpanton, the great master of the Castilian yeshiva, he was a rosh yeshiva, preacher and physician. He first taught in Toledo and later moved to Lisbon to found his own yeshiva.

With the expulsion from Spain in 1492 his family reached Portugal; in 1497 the decree forcing Jews to convert or leave the kingdom sent him wandering again. On the way to Turkey he suffered terrible calamities: all his sons perished. He settled in the Ottoman Empire, between Istanbul and Magnesia, where he preached before the communities. There he took in and raised his nephew Yosef, orphaned of his father, the future author of the Shulchan Aruch, who grew up in his home and consulted him on halachic questions.

In 1517 he sent his major work, Toldot Yitzchak, to press: a collection of sermons on the Torah combining plain meaning and allegorical interpretation, which his nephew quotes several times. His students also compiled his sermons on philosophy and aggadah as Chasdei David, and some of his responsa appear in Rabbi Yosef Karo's Avkat Rochel.

That same year he set out for the Land of Israel; according to some traditions he stayed in Damascus, according to others he reached Safed. He passed away around 1535.