Sub-Saharan urban centers have to tackle high population growth, lack of sanitation infrastructures and the need for good quality water resources. To characterize the impacts of anthropization on the water resources of the capital of Cameroon (Yaoundé), a multi-disciplinary approach was used in ten sub-watersheds (peri-urban and urban) of the Méfou watershed. Pharmaceutical residues were used as tracers of surface and groundwater contamination caused by the release of domestic wastewater from pit latrines and landfills. A water use survey was conducted in the vicinity of the sampling sites to better assess water use, treatment and management. Available land use and hydro-geomorphological data completed characterization of the sub-watersheds. The combined data showed that natural features (elevation, slope, and hydrography) and human activities (land use) favor rainfall-runoff events and hence surface water contamination. Pharmaceutical monitoring revealed contamination of both surface and groundwater especially in the urban sub-watersheds. Analgesics/anti-inflammatory drugs and anti-epileptic carbamazepine were the most frequently found compounds (in up to 91% of water samples) with concentrations of acetaminophen reaching 5660 ng/L. In urban sub-watersheds, 50% of the groundwater sites used for drinking water were contaminated by diclofenac (476–518 ng/L), carbamazepine (263–335 ng/L), ibuprofen (141–276 ng/L), sulfamethoxazole (<2–1285 ng/L) and acetaminophen (110–111 ng/L), emphasizing the need for a deeper understanding of the interactions between surface and groundwater. The use of groundwater as drinking water by 68% of the total population surveyed raises concerns about population exposure and potential health risks. This case study highlights the need for strategies to limit contamination of the water resource given the predicted future expansion of Sub-Saharan urban centers.