Before European settlement, the land was part of the traditional territory of Native American tribes, including the Shawnee, who used the dense forests and waterways for hunting, fishing, and travel.

Early indigenous use of the region is tied to the larger Appalachian culture, which developed over thousands of years and relied on the area's abundant natural resources.

Artifacts and traces of indigenous activity suggest that the area was intermittently inhabited or utilized for centuries, with the region's rich biodiversity providing ample resources for local tribes.

[4] Surveys of Otter Creek Wilderness and adjacent areas, including the Fernow Experimental Forest, have documented over 460 species of vascular plants across 94 families.

These species likely established themselves through historical land use practices, including logging, farming, and roadbuilding, which disturbed the landscape and created opportunities for invasive plants to spread.

While specific studies on fauna within Otter Creek are limited, the surrounding Monongahela National Forest is known to host black bears, white-tailed deer, wild turkeys, and various small mammals, birds, and amphibians.