The Rio Santo Antônio rises in the Espinhaço Mountains, in the district of Santo Antônio do Cruzeiro within the municipality of Conceição do Mato Dentro, in Minas Gerais. From its headwaters it runs eastward for approximately 287 kilometers before emptying into the Rio Doce. The river drains a basin that includes several municipalities in the region.

The river is characterized by a rocky course with a significant number of waterfalls, which define much of its paddling character. Among the most notable is the Cachoeira do Tabuleiro, rated in the 2005 edition of the Guia 4 Rodas as the most beautiful waterfall in Brazil. The presence of multiple falls and rocky sections means paddlers should exercise caution and scout drops carefully, as these features represent significant hazards on any downstream run.

The river has historical significance as a route used by bandeirantes during the Brazilian Gold Rush, and it continues to support fishing and gold panning alongside leisure and tourism activities. The combination of a rocky, waterfall-laden course and active recreational use means paddlers are likely to encounter other users on the water.