Don Yitzchak ben Yehudah Abarbanel was born in Lisbon in 1437 into one of the oldest noble families of Iberian Jewry, which by family tradition traced its descent to King David. He studied Torah with Rabbi Yosef Chayun, the rabbi of Lisbon, and philosophy with Rabbi Yosef ibn Shem Tov. While still young he wrote Ateret Zekenim and Tzurat HaYesodot.

Like his father before him, he served as treasurer to King Afonso V of Portugal. He used his wealth to help his people: in 1471 he ransomed 250 Jewish captives from Arzila in Morocco and provided for them for two years. Accused of treason in 1483, he fled to Castile, and King John II confiscated all his property. In Castile he resumed his Bible commentary, and for eight years he administered the finances of Ferdinand and Isabella.

In 1492 he tried in vain, through pleas and offers of large sums, to have the edict of expulsion revoked, and then went into exile with his people. In Naples he advised King Ferdinand I; during the French invasion he lost his possessions and part of his library. He passed through Corfu, settled in Monopoli in 1496, where he completed Zevach Pesach on the Haggadah, and in 1503 moved to Venice, where he mediated between the Republic and Portugal.

His commentaries on the Torah and the Prophets, each chapter opening with a list of questions that he answers methodically, are still widely studied. He forcefully defended the creation of the world and the messianic hope. Works: commentaries on the Torah and the Prophets, Zevach Pesach, the messianic trilogy (Mayenei HaYeshuah, Yeshuot Meshicho, Mashmia Yeshuah), Rosh Amanah, Ateret Zekenim.

He passed away in Venice in 5269 (1508), aged seventy-one. Since Jews could not be buried in Venice, he was buried in Padua, next to Rabbi Judah Minz. The cemetery was destroyed during the siege of Padua in 1509, and the exact location of his grave is unknown.