Despite the disgrace of his previous voyage, Columbus was granted a fourth and final expedition by the Spanish Crown. He departed from Cádiz with four ships, aiming to find a passage to the Indian Ocean through the newly discovered lands.

Columbus arrived off the coast of Santo Domingo (Hispaniola), but he was denied entry to the harbor by the new governor, Nicolás de Ovando, despite warnings of an impending hurricane. This denial forced Columbus to seek shelter elsewhere.

Columbus explored the coasts of present-day Honduras, Nicaragua, Costa Rica, and Panama, searching for a passage to the Indian Ocean. He encountered various indigenous cultures and engaged in trade and conflict with them.

Columbus attempted to establish a settlement in Panama, but it was short-lived due to hostile indigenous populations and internal conflicts among the Spanish settlers. This marked a setback for the expedition.

Columbus's ships became severely damaged and were eventually shipwrecked off the coast of Jamaica. He and his crew were stranded on the island for over a year, relying on the goodwill of the indigenous population.

After months of hardship, Columbus and his crew were rescued from Jamaica by a ship sent from Santo Domingo. He returned to Spain, weakened and disillusioned.