The first European to reach Juazeiro was probably Belchior Dias Moréa; he had left Rio Real for Barra do Rio Grande in 1593 and from there descended the São Francisco River to Juazeiro, arriving some three years later. By the early seventeenth century most of the backlands were under the control of the García d'Avila family. In 1658 the head of the family, Francisco Dias d'Avila, and his uncle, Father Antônio Pereira, obtained land grants including the present municipality of Juazeiro along the São Francisco River. Effective control and colonization of the area, however, were possible only after years of struggle with the Indian inhabitants. The second Francisco Dias d'Avila was able to repress Indian resistance by June 1676. By the end of the seventeenth century, Juazeiro had emerged as the center of the lower and middle segments of the São Francisco Valley because of its strategic location at the crossroads of two old passageways of the interior: the river and the land route of the early explorers, including Paulistas under the domination of Domingos Sertão, Bahians under García d'Avila, Pernambucans under Francisco Caldas, and Portuguese under Manuel Nunes.

In 1766 Juazeiro was classified a vila or town under the jurisdiction of the comarca, or judicial district, of Jacobina (and in 1857 under the comarca of Juazeiro). This important step in Juazeiro's political and administrative evolution was the result of the efforts of Captain General Antônio Rolim de Moura Tavares, count of Azambuja.