In addition to the endangered species mentioned above, the refuge provides habitat for a variety of migratory and resident wildlife species. One hundred and sixty bird species have been sighted on the refuge. Several bird species commonly seen during the breeding season include dickcissels, grasshopper sparrows, field sparrows, and northern bobwhite, which are indicative of the native grasslands and early successional habitats found on the refuge. Northern harriers can be seen flying low over refuge grasslands searching for prey during the winter months. Short-eared owls can also be seen occasionally in grasslands during the winter. Other commonly seen wildlife species include cottontail rabbits, coyotes, white-tailed deer, gray squirrels, eastern meadowlarks, horned larks, and eastern bluebirds.

Key Cave lies on the northern shore of Pickwick Lake in a limestone karst area that contains numerous sinkholes and several underground cave systems. The areas sinkholes are an integral component of groundwater recharge for the cave. In 1990, the Ozark Underground Laboratory determined the underground recharge area by the use of dye traces. The recharge area was divided into four potential risk areas: high hazard, moderately high hazard, moderate hazard, and low hazard.

The Monsanto Company owned a large 1,060 acre tract in the high hazard risk area that was identified by conservationists as in need of protection and in 1992 sold this tract to The Conservation Fund. The Conservation Fund held the land until the U.S. Fish and Wildlife Service bought the land five years later to establish Key Cave NWR, which became part of the National Wildlife Refuge System on January 3, 1997.