The river rises from springs in northeastern Kerr County, approximately 25 miles (40 km) southeast of Junction.

The river has a close association with the Texas Hill Country, tied to the history of the region and emblematic of its geography.

In 1750, Fray Benito Fernández de Santa Ana proposed a plan to the Spanish government that a mission be established among the Lipan Apache who lived along the river.

In 1789, the river was the site of a skirmish between Colonel Francisco Xavier Ugalde and a group of Lipan and Mescalero Indians.

Pedernales Falls State Park is located along the river in Blanco County east of Johnson City.