Parts of Selous Game Reserve were set aside as early as 1896. However, it was not until 1922 that it was expanded and given its present name (after Frederick Courteney Selous, the British explorer who was killed and buried in the reserve during WWI, and whose grave can still be visited). The area continued to be extended until 1975 when it assumed its current boundaries.

During the 1990s and thereafter, efforts were initiated to link Selous Game Reserve with the Niassa Reserve in Mozambique, with the first stages of the project – including establishment of a wildlife corridor – already functional.

Much of this progress is gradually being reversed by more recent developments within the reserve. These include poaching, uranium mining in the southern part of the Selous (leading to a redrawing of reserve boundaries) and government confirmation in mid-2017 that the Rufiji River – the heart and lifeblood of the Selous – will be dammed near Stiegler's Gorge, in the northwestern part of the reserve, in connection with a planned hydroelectric project.

In 2014 Unesco placed the Selous on its World Heritage in Danger list, and it reconfirmed this decision in 2017. If the dam project moves forward, complete delisting in the near future is a very real possibility. The Selous' only hope for survival now rests in the ability of concerned environmentalists in Tanzania and beyond to convince the government that it can achieve its goals of increasing Tanzania's electrical grid capacity and overall economic health through means other than exploiting one of its greatest natural treasures.