An integrated approach involving geological, borehole data, hydrogeochemical and environmental isotope analyses was used to determine the groundwater potential of the eastern Kalahari region of South Africa, an area to the west of Mahikeng that stretches northward from the Orange River into Botswana. The total groundwater resource potential for the eastern Kalahari region of South Africa is estimated at 10127 Mm3/a, with the Kalahari Group aquifer showing the greatest potential, comprising 51% of the total resource. The storage capacity of the Kalahari Group aquifer (7130 Mm3) is also impressive, estimated to be more than twice that of the dolomite aquifer (2728 Mm3). Despite having such great potential, the aquifer is not actively recharged and is often associated with very saline water that is not suitable for human and livestock consumption. The limestone and dolomite aquifers of the Campbell Rand Subgroup, as well as the weathered granitic rocks of the Archaean basement, are considered as the most prospective water bearing formations, with a groundwater resource potential estimate of 1981 Mm3/a and 1845 Mm3/a, respectively. Aquifers with the least potential in the project area comprise the fractured basement rocks of the Kraaipan - Amalia greenstone belt, with a groundwater resource potential of 26 Mm3/a, and the fractured sedimentary rocks of the Asbestos Hills Subgroup, with a groundwater resource potential of 108 Mm3/a. The calculated groundwater storage and resource potential in the eastern Kalahari region of South Africa satisfies a large proportion of the water demand in the region.