Originally established as a forest reserve in 1932, Semuliki was designated a national park in 1993 to help prevent deforestation. It's often confused with the adjacent Semliki Wildlife Reserve. The park's forests are an extension of the Ituri Forest, which stretches into Central Africa, meaning many of the tree and animal species found in Central Africa also exist in Semuliki. The park's environment is unique compared to other parks in Uganda, Kenya, or Tanzania, with conditions more akin to those in Central Africa.

Semuliki is known for being one of the top birdwatching destinations in Uganda, home to over 410 bird species. About 67 percent of these are forest birds, including the Blue-headed Crested Flycatcher, Capuchin Babbler, and White-tailed Hornbill. Due to its connection with the DR Congo forest, the park also hosts species like the Black-wattled Hornbill and Congo Serpent Eagle.

The park is also home to 60 species of mammals, such as the bay duiker, flying squirrels, forest buffalos, pygmy hippos, and leopards. There are about 300 species of butterflies and eight species of primates, including chimpanzees, blue monkeys, and olive baboons. Night primates like pattos and galagos also inhabit the park.

Despite its rich biodiversity, Semuliki faces threats from human activities. Local communities, including the Bamba and Bakonjo tribes, rely on the park's resources, hunting animals for meat and gathering herbs, vegetables, and firewood. This encroachment continues to pose a threat to the park's wildlife and forests.