Diego de Nicuesa was a Spanish conquistador and explorer. In 1506, he was given the job of governing Costa Rica, but ran aground off the coast of Panama. He made his way north overland, against resistance from the native population. The combination of guerrilla warfare and tropical disease killed half his expedition before he gave up.

Around 1509, under a land grant from the Spanish king, he became founder and governor of the colony of Castilla del Oro, in what is now Panama, one of the first two Spanish settlements on the American mainland (different sources give dates from 1508 to 1510).

In 1511, Vasco Núñez de Balboa, seeing Nicuesa as a rival for possible fame and fortune that would go to the Spaniard who found a route across the Isthmus of Panama, set Nicuesa adrift on an un-seaworthy boat; he and his crew drowned.