Rapid and uncontrolled urbanization in sub-Saharan Africa has led to an increased production and expansion of synthetic chemicals, resulting in significant pollution of the aquatic environments, particularly by Emerging Organic Contaminants (EOCs). Due to the low income of the population in this region, there is often a lack of control over water and fishery resources prior to consumption. Therefore, the current study aims to use EOCs as markers of water resource quality degradation, and to assess the potential environmental risk of these compounds on some aquatic organisms. Among 120 targeted compounds, 66 were detected at 22 sites in Douala city, Cameroon, including 9 rivers and 13 groundwater samples. The detected EOCs were classified into three categories, including pharmaceuticals and personal care products (n = 55), lifestyle compounds (n = 7) and industrial compounds (n = 4). Surface water was highly impacted, with EOC total concentrations reaching 61,273 ng/L, versus 16,677 ng/L in groundwater. Contamination levels and the type of contaminants were closely linked to land use patterns in the study area. Contamination was mainly attributed to domestic, hospital and brewery's industry wastewaters, landfill and pit latrines. Consumption patterns and physicochemical properties of compounds, in particular their persistence, polarity and octanol/water gradient (Kow), explain their occurrence at high concentrations (up to μg/L) in groundwater. According to Risk Quotient (RQ) with a maximum of 93.4 in surface water and 8.5 in groundwater, about 1/3 of the identified compounds pose a serious threat to aquatic organisms, including algae, invertebrates and fish. For the first time in Central African, we revealed these high levels of water contamination by EOCs and identified the risk for the environmental health. Our study demonstrates the urgency to adopt sustainable water management strategies in large cities of the region.