The Madikwe Game Reserve is home to a multitude of different mammals, birds, reptiles and amphibians. There are over 80 different mammals living on the game reserve, and an array of the different bird species, snakes, tortoises, terrapins, lizards and frogs can be found on the game reserve.

The game reserve's climate is particularly warm and humid during the rainy season between October and April, while visitors can expect dry weather with cold temperatures at night during the dry season between May and September.