The arrival of Columbus at Cadiz, in chains, produced almost as great a sensation as his first triumphant return. A general burst of indignation arose. The sovereigns sent orders that he should be instantly set at liberty, and promised that Columbus should be reinstated in all his dignities. But Ferdinand repented having invested such great powers in any subject, and especially in a foreigner. Plausible reasons were given for delaying his reappointment, and meanwhile Don Nicholas de Ovando was sent out to supersede Bobadilla.
Columbus's thoughts were suddenly turned to a new enterprise. Vasco da Gama had recently reached India round the Cape of Good Hope, and immense wealth was poured by this route into Portugal. Columbus was persuaded that the currents of the Caribbean Sea must pass between Cuba and the land which he had discovered to the south, and that this route to India would be more easy and direct than that of Vasco da Gama. His plan was promptly adopted by the sovereigns, and he sailed in May 1502, on his last and most disastrous voyage. He steered to Hispaniola, but was not permitted to land, and then coasted along Honduras and down the Mosquito Coast to Costa Rica. Here he found gold among the natives, and heard rumours of Mexico. He continued beyond Cape Nombre de Dios in search for the imaginary strait, and then gave up all attempt to find it.
Possibly he knew that another voyager, coasting from the eastward, had reached this point. He turned westward to search for the gold-mines of Veragua, and attempted unsuccessfully to found a settlement there. As his vessels were no longer capable of standing the sea, he ran them aground on Jamaica, fastened them together, and put the wreck in a state of defence. He dispatched canoes to Hispaniola, asking Ovando to send a ship to relieve him, but many months of suffering and difficulty elapsed before it came.
Columbus returned to Spain in November 1504. Care and sorrow were destined to follow him; his finances were exhausted, and he was unable, from his infirmities, to go to court. The death of Isabella was a fatal blow to his fortunes. Many months were passed by him in painful and humiliating solicitation for the restitution of his high offices. At length he saw that further hope of redress from Ferdinand was vain. His illness increased, and he expired, with great resignation, on May 20, 1506.