Amphion was settled in the late 1880s, and had a post office from 1881 to 1916. It served as the first county seat of Atascosa County. In 1896, the population was reported as 100, and by 1904 the local public school had 72 students and two teachers. Amphion's decline began in 1909 when the Artesian Belt Railroad (from Macdona to Simmons City) bypassed it in favor of Jourdanton. In the 1940s Amphion still had a school, a cemetery, and a few dwellings, and by 1956 it was described as a ghost town. In the late 1960s only the cemetery and a few buildings remained. In 2000 the population was twenty-six.
The soil series known as "Amphion clay loam", classed as a fine, mixed, superactive, hyperthermic Pachic Paleustoll, is named after the town.