Water quality assessment for water resource protection and management is key towards sustainable provision of potable water supply and in meeting sustainable development goals (SDGs) linked to clean water and sanitation. The spatial and temporal aspects of groundwater quality in the Nseleni catchment, South Africa (SA) was investigated, its suitability for domestic use was considered, and required protection measures were established. Using a hybrid approach methodology based on multiple water quality resource assessment techniques such as groundwater quality index (GQI) and concentration duration curves (CDCs), 72 groundwater samples collected from 1994 to 2017 were analysed for physico-chemical (Na+, Ca2+, Mg2+, Cl−, SO42−, NO3−, F−, EC, pH) parameters. Approximately, 33.3% of groundwater samples in the Nseleni catchment were found suitable for drinking when compared to South African water quality guidelines. The use of a hybrid approach method showed that overall groundwater quality in the study catchment was classified as excellent for domestic water use when the groundwater quality index was calculated to be 39.11. Groundwater quality reserve limits for groundwater resources protection were determined for the nine water quality parameters using CDCs. The study concluded that using groundwater quality index and concentration duration curves, it was feasible to classify groundwater resources for improved groundwater quality of reserve determination in the South African context. The study recommends the application of the hybrid method in various catchments of similar characteristics to the studied catchment for setting groundwater quality limits that would contribute towards achieving the goal of groundwater resources protection in other catchments.