Its upper portion in Guinea is known as the Diani River or Niandi River, and forms part of the boundary between Guinea and Liberia.

The river became important for the slave trade: Robert Bostock established a factory here.

Because the soil around Monrovia, Liberia was poor and the coastal areas were covered in dense jungle, many early African-American emigrants to Liberia in the 19th century moved up to the nearby St. Paul River, where they found land suitable for agriculture.

Also, American Lutheran missionaries set up the Muhlenberg Mission Station along the river, where they taught children various academics, technical/agricultural skills (especially the cultivation of coffee), and catechism.

Day introduced a steam ship to the river for the purposes of commerce and travel.