Little is known of Po’pay’s life before 1675. In that year he was imprisoned by Spanish authorities on suspicion of witchcraft and of killing several missionaries. Since the expedition led by Francisco Vázquez de Coronado that had begun Spanish colonization of the Southwest in 1540, hundreds of Pueblo individuals had been impressed into virtual slavery or, if they dared open resistance, executed. (The staff of the missions and garrisons established by the Spanish were often cruel and wanton; their own records indicate that they frequently engaged in beatings, maiming, rape, and other forms of torture, as well as execution by burning at the stake.) After his release from prison, Popé hid in Taos Pueblo to plan and organize what came to be known as the Pueblo Revolt. Popé believed that he was commanded by tribal ancestral spirits (kachinas) to restore traditional native customs, and other villages enthusiastically responded to news of the planned uprising.
On August 10, 1680, Po’pay led a united attack of almost all the Pueblo Indian tribes on the Spanish capital of Santa Fe, killing nearly 500. After 10 days nearly 1,000 besieged residents abandoned the city and fled to El Paso del Norte. Popé immediately set about erasing all vestiges of Spanish culture and the Christian religion. Restoring ancestral ways, he traveled from one pueblo to another in ceremonial dress. For a time he was accorded great honour, but success made him despotic, and, after a few years, drought, enemy tribe forays, and internal dissension combined to depose him. He was, however, reelected Pueblo leader in 1688, shortly before his death. Although Spanish rule was reestablished in 1692, the alien domination was never as strong as before the time of Popé.