Columbus married Filipa Moniz Perestrelo, a noblewoman from a Portuguese family. Her father, Bartolomeu Perestrelo, was a captain in the service of Prince Henry the Navigator and the governor of Porto Santo Island. This marriage provided Columbus with access to influential circles and valuable maritime information.

Diego Columbus, Columbus's first son, was born in Lisbon around 1480. Diego later became the 2nd Admiral of the Indies, 2nd Viceroy of the Indies, and 4th Governor of the Indies, continuing his father's legacy in the New World.

After his wife Filipa's death, Columbus had a relationship with Beatriz Enríquez de Arana, a woman from Córdoba. The exact circumstances of their relationship are not well documented, but it resulted in the birth of his second son.

Ferdinand Columbus (also known as Hernando Colón) was born to Columbus and Beatriz Enríquez de Arana in Córdoba. Ferdinand became a renowned scholar, cosmographer, and biographer of his father. He amassed a vast library and played a significant role in preserving his father's legacy.

After Columbus's death, his son Diego inherited his titles and continued to pursue his father's claims. Diego married María de Toledo y Rojas, a niece of the Duke of Alba, further solidifying his position within the Spanish nobility. Diego and Maria had several children, including Luis Columbus, who later relinquished his family's rights and titles in exchange for land and a ducal title.

Columbus's descendants continued to be involved in Spanish society, holding various titles and positions. Ferdinand Columbus's extensive library, the Biblioteca Colombina, became a valuable resource for scholars studying the Age of Exploration and Columbus's voyages. Though the direct line eventually faded from prominence, their historical significance remains.