Agüeybaná, believing that the Spaniards were gods, received the Spanish conquistador Juan Ponce de León with open arms upon his arrival in 1508. According to an old Taíno tradition, Agüeybaná practiced the "guatiao", an old Taíno ritual, in which he and Juan Ponce de León became friends and exchanged names. Ponce de León then baptized the cacique's mother into Christianity and renamed her Inés. The hospitality and friendly treatment that the Spaniards received from Agüeybaná made it easy for them to conquer the island.
The cacique joined Ponce de León in the exploration of the island. After this had been accomplished, Agüeybaná accompanied the conquistador to the island of "La Española" (What today comprises the nations of the Dominican Republic and Haiti), where he was well received by the Governor Nicolás de Ovando. Agüeybaná's actions helped to maintain the peace between the Taíno and the Spaniards. The peace between the Spaniards and the Taínos' was short-lived. The Tainos were forced to work in the island's gold mines and in the construction of forts as slaves. Many Taínos died as a result of the cruel treatment which they received.
Agüeybaná II, organized a revolt and under his leadership, the Taíno people raided many of the Spanish settlements. However, Agüeybaná II's people, who were only armed with spears,bows, and arrows, were no match for the better armed Spanish forces. When Agüeybaná II faced the forces of his brothers former "friend", Ponce de León, in 1511, he was shot dead. The revolt failed and many Taínos either committed suicide or left the island. Many of those who stayed on the island soon died of either the cruel treatment that they had received or of the smallpox epidemic, which had attacked the island.
Many songs and poems, by poets such as Juan Antonio Corretjer, among others, have been written about Agüeybaná.