It is a major tributary of the East Fork of the White River and drains 1,000 square miles (2,600 km2).

In one area it serves as the southern boundary of the main unit of the Muscatatuck National Wildlife Refuge.

[6] The path of the Muscatatuck was formed by valley beds created during an ice age.

The first documented Europeans arrived in 1818, although it is possible that squatters lived in the area before Indiana's 1816 statehood.

[14] Noted Hoosier artist T. C. Steele particularly loved using the Muscatatuck River in his paintings.