The refuge was established March 26, 1930 by executive order of President Herbert Hoover and contains 32,080 acres (130 km2) of protected land as habitat to approximately 312 species of birds and 30 species of mammals. It was designated a National Natural Landmark in June 1983.
The Salt Plains were a favorite hunting ground for American Indians. Bison and other game came to the area to eat the salt and the heavily wooded and well-watered area along the Salt Fork River was like an oasis in the surrounding grassland of the Great Plains. Salt Plains refuge is divided into almost equal areas of non-vegetated salt flat, open water, and vegetated land. Marshes, woods, grassland, and cropland dot the refuge. Management tools used to enhance the habitat for wildlife include farming, grazing, prescribed burns, construction of ponds, and wetland draining and flooding.
The refuge was created to be a resting and breeding ground for migratory waterfowl especially during fall and spring. The entire refuge is designated as critical habitat for the endangered whooping crane, which is mostly seen during fall migration. In addition, the refuge is home to endangered least terns, threatened snowy plovers, threatened bald eagles and peregrine falcons. Large populations of American white pelicans migrate through between August and September, staying on the Great Salt Plains Reservoir. Great Salt Plains is one of the most important habitats for shorebirds in the Western Hemisphere.
Ralstin Island (closed to the public) is an important rookery in the Great Salt Plains Lake. The island was originally 25 acres (100,000 m2), but has eroded to about 6 acres (20,000 m2). It hosts more than 30,000 birds during breeding season. Over 30 species nest in the colony, including the white-faced ibis, great blue herons and most notably, the tricolored heron.
In 2007, a Boy Scout digging for crystals uncovered a collection of 7.5-inch vials containing chemical agents such as mustard gas, lewisite, chloropicrin, and phosgene. The vials were part of World War II era military Chemical Agent Identification Sets. The burial of vials was standard procedure for removing them from service at that time. There was no record of a disposal site at the salt plains. Crystal digging was suspended from April 2007 until April 2009, while the risk of allowing digging again was evaluated. 171 vials and at least a dozen incendiary devices were removed from the location. The salt plains were also used as a bombing and strafing range during World War II. There are still remnants of this use left on the plains.