The reintroduced wildlife has flourished and Madikwe now boasts not only the Big Five, but also a thriving population of African wild dog. Large numbers of elephant, giraffe and impala occur alongside oryx, springbok and red hartebeest. Both spotted and brown hyena are found in the reserve. Classed as a semi-arid region, most of the rain at Madikwe occurs between November and March in the form of short, sharp thundershowers in the late afternoon. The average daytime temperature is 25°C/77°F, although extremes of up to 40°C/104°F can occur. Winters are cool and dry, with cold nights when the temperature can drop to below freezing.

The northern parts of Madikwe are dominated by flat, open plains that are a legacy of the former farmlands that the land is made up of. These open areas provide excellent game viewing opportunities and are favoured by species such as springbok, blue wildebeest and white rhino. Apart from grasses and small shrubs, various species of acacia tree are the dominant vegetation in these flat regions. The leaves and seed pods of the acacia are very popular with browsing species, while the sweet grasses attract the grazers. Porcupines can also often be seen digging out acacia leaves.

Small, lone-standing rocky hills called inselbergs are scattered in the north of the reserve. These stony outcrops form the perfect habitat for klipspringer and rock hyrax, while leopard and brown hyena search out caves for use as den sites. The Dwarsberg Hills form a natural barrier between the flat areas in the north and south of Madikwe. These low hills, with their diverse vegetation, provide the ideal environment for kudu, bushbuck, eland, black rhino, spotted hyena and leopard. The perennial Marico River forms the western boundary of Madikwe, but is not the reserve's only source of water. A number of dams provide drinking water throughout the year and serve as focal points for elephant, buffalo and rhino.