It was founded on March 5, 1749, with the dedication to Señora Santa Ana by captain Don Blas María de la Garza Falcón at the eastern edge of the San Juan River near its confluence with the Río Grande.

After establishing other towns in the interior of Mexico between Querétaro[citation needed] and the Gulf coast, José de Escandón arrived at Camargo on March 3, 1749.

At the location called, "Paso del Azucar" on the Rio Grande, about two leagues southeast of the present site of Camargo, he met Captain Blas Maria de la Garza Falcón who already had been encamped there with forty other families and some soldiers.

The town had already been laid out on the eastern bank of the San Juan River, not far from the Rio Grande, and temporary shelters made, jacales (straw huts).

Father Fray Hierro, who had joined Escandon at Padilla and was a missionary from the college of Zacatecas, kept a diary which provides many interesting details concerning the establishment of the first settlements of the Lower Rio Grande Valley.