Kyambura Wildlife Reserve lies immediately south of Lake George, and east of Queen Elizabeth National Park where the Kazinga Channel leaves the lake, flowing towards Lake Edward. Although Kyambura Wildlife Reserve has similar ecosystems to Queen Elizabeth National Park, the natural barriers formed by the Kyambura Gorge and Kazinga Channel make it possible to manage the area as a separate entity. Kyambura Wildlife Reserve serves as a buffer zone for the north-eastern part of Queen Elizabeth National Park. There is no land connection between the reserve and the park, animals simply fording the Kyambura river where it is shallowest during the dry seasons to move between the protected areas. The river gorge supports a high-canopy tropical forest which grades to a swamp-forest and papyrus (Cyperus papyrus) swamp near the river mouth. The eastern border follows Buhindagi river from Lake George, south-east to Kasyoha-Kitomi Forest Reserve where the boundaries of the Forest and Wildlife Reserves abut. A road from the main Mbarara–Kasese highway runs up to Kashaka fish-landing site, bisecting the reserve. There are seven volcanic crater-lakes, both fresh and saline, in the reserve, the most significant of which are the saline Lakes Nshenyi, Bagusa and Maseche; Lakes Chibwera, Kinera, Kararo and Kyamwiga have fresh water.

The fauna and flora are similar to that of Queen Elizabeth National Park). Both Important Bird Areas have volcanic craters with saline lakes, which are important sites for waterbirds. A total of 332 bird species has been recorded in Kyambura Wildlife Reserve including seven species of global conservation concern. Lake George, the Kazinga Channel and the seven crater-lakes within the reserve offer a large and varied habitat to many birds, including about 110 wetland species. Lakes Maseche, Nshenyi and Bagusa are within a few kilometres of each other, and the populations of Phoenicopterus minor in these craters can be considered as one. Since 1994, the number recorded on the three saline lakes together has exceeded 20,000 on several occasions, and reached 30,000 in February and August 1999. Although the population of Phoenicopterus minor in Uganda is only 2% of the total population in East Africa, these sites are of considerable conservation importance, since they represent alternative potential breeding sites if the traditional breeding sites are not available. Laniarius mufumbiri and Chloropeta gracilirostris were recorded in papyrus swamps along the shores of Lake George in November 2000. There is a roosting site for Pelecanus onocrotalus at Kashaka fishing village, with a single count of 900 birds in 1994.

Apart from the bird species in the reserve, there are also threatened mammals including Loxodonta africana (EN), Panthera leo (VU) and Pan troglodytes (EN).