Rising in northern California, it soon crosses the border and flows northeast then northwest to meet the Rogue about 6 miles (9.7 km) west of Grants Pass.

The Applegate River's headwaters are located in the Siskiyou Mountains in California, part of the Rogue River–Siskiyou National Forest.

[6] The river then flows north through a steep canyon past the Oregon-California border, receiving water from Elliot Creek.

[7][8] Elliot Creek begins near Dutchman Peak in Oregon, before flowing southwest into California, roughly paralleling the border.

[7][9] The United States Army Corps of Engineers began construction of the dam in 1974, and it was completed in 1980.

[6] The most common trees within the Applegate River's watershed include Douglas fir and madrone.

[13] Oregon white oak and big-leaf maple grow in the loam soil found on the higher slopes.

[13] Animals that live along the Applegate River include the endangered Siskiyou Mountains salamander, and the near threatened spotted owl.