The park's stategic geographic location and varied habitats are largely responsible for its high faunal diversity. More than 140 species of vertebrates, including at least 44 mammals, 75 birds, 11 amphibians, 9 fish and 3 reptiles are seasonal or permanent residents. The many species of invertebrates have yet to be inventoried.

Large forest mammals in the park include cougar, bobcat, black bear, coyote and black-tailed deer (Odocoileus hemionus columbianus). A resident herd of Roosevelt elk (Cervus elaphus roosevelti) frequently browse park forests and willow swamps in winter and graze nearby fields in summer. Elk figure prominently in Fort Clatsop's history from the time of Lewis and Clark. The abundance of elk was a critical factor in the explorers' decision to winter in the region.

Smaller denizens of the forest include six sensitive bat species and the white-footed vole (Arborimus albipes), a federal species of concern. These nocturnal mammals share the canopy with northern flying squirrels (Glaucomys sabrinus sabrinus), western red-backed voles (Clethrionomys californicus) and other mature forest inhabitants. A large number of resident and migratory birds are found in the park in all seasons, due to its mild climate, diverse habitats and location on the Pacific flyway. Peregrine falcon (Falco peregrinus anatum) and bald eagles (Haliaeetus leucocephalus) nest on seacliffs and giant spruce at Cape Disappointment, and threatened marbled murrelets (Brachyramphus marmoratus) have been documented in areas of old growth forest there. Band-tailed pigeons (Patagioenas fasciata) and olive-sided flycatchers (Contopus cooperi), two federal species of concern, seasonally inhabit park coniferous forests, along with resident pileated woodpeckers (Dryocopus pileatus), many songbirds and several owl species. Forest streams and swamps are home to a number of amphibians, including sensitive northern red-legged frogs (Rana aurora aurora) and eight species of salamanders. Remote coldwater streams at Cape Disappointment harbor sensitive Cope's giant salamanders (Dicamptodon copei) and Columbia torrent salamanders (Rhyacotriton kezeri). The torrent salamanders, along with rare Pacific giant salamanders (Dicamptodon tenebrosus) are also found in forest streams in the Fort Clatsop unit.

Extensive estuarine wetlands within the park provide valuable rearing habitat for threatened and endangered salmon and steelhead (Oncorhynchus species), as well as being home to coastal cutthroat trout (Oncorhynchus clarki clarki) and lamprey (Lampetra species). Estuarine projects in 2006 are restoring an entire stream ecosystem and improving salmonid habitat at Fort Clatsop. Many birds and mammals are also at home in the park's estuarine wetlands. Bald eagles, osprey (Pandion haliaetus), river otter (Lutra canadensis) and a variety of hawks, waterfowl and shorebirds are commonly spotted from the newly completed Netul Trail along the Lewis and Clark River. Eagles nest in a large spruce near Netul Landing and are often seen in flight or perching along the river. As a result of protection and the banning of DDT, these formerly endangered birds are making a strong comeback in the Columbia River estuary. Endangered brown pelicans (Pelecanus occidentalis californicus) may be seen flying in formation over the offshore waters of the park's coastal units in late summer.  Reptiles found in various park habitats include the northwestern and common garter snakes (Thamnophis ordinoides and T. sirtalis) and the northern alligator lizard (Elgaria coerulea).

Several nonnative vertebrate pest species, including black rats, opossum, nutria, starlings, and bullfrogs also inhabit some areas of the park.

Approaching, feeding, hunting or removing wildlife from the park is illegal. A current state fishing license is required to catch fish in the Lewis and Clark River, and Oregon and Washington established fishing seasons must be observed.