Isabella's marriage to Ferdinand of Aragon united Spain's two largest kingdoms and laid the foundation of the Spanish state. They governed independently, however, and Isabella initiated a program of reform which reduced the power of her rebellious nobles, streamlined her government, and encouraged scholarship.

Intensely religious, she helped establish the Inquisition in Andalusia, which led to the expulsion from Spain of over 170,000 Jews. With Ferdinand, she conquered Granada, the remaining territory of the Moors. Eventually, they too were expelled from Spain.

Isabella sponsored the voyages of Columbus, which gave Spain its first claims in America.