Water is an essential element for humankind, animals, and plants. It is also an important element of the aquatic environment (the natural habitat of multiple species), where its quality plays a determining role in their protection and conservation. Unfortunately, the water quality of natural environments has worsened in the last decades. In sub-Saharan Africa and particularly in Bénin, in contrast to river discharges, monitoring the quality of surface water is a very rare activity. Thus, knowledge about physical and chemical properties as a basis for evaluation of the state of the environment and protection measures needed is almost absent. This article presents the results of the first structured, regular monitoring campaign on surface waters in the whole basin of the Ouémé River in Bénin Republic. With 510 km, the Ouémé River’s water quality fluctuates from upstream (Taneka Koko mountains in the north) to downstream (gauging station Bonou in the south) sources. This is due to soil erosion, lack of water treatment plants, and the use of significant quantities of fertilizer in the cotton zone. The present research was initiated to study the resource degradation of this area through chemical and physical water analysis. The monitoring of water quality has been followed for 5 years on twenty physicochemical parameters, from samples taken at four gauging stations on the main channel of the Ouémé River. Means and standard deviations of water analysis results were compared to both the recommendations of the World Health Organization (WHO) and the Maximum Permissible Concentrations (MPC) for drinking water (WHO 1987). Thus, high values were observed for physical parameters, i.e., color and turbidity had peaks of 697.5 uC and 129 FTU at Bétérou station in the wet season, although certain parameters, such as total hardness, present low values compared to the recommended standards. Moreover, excluding the concentrations of NO2 − and NH4 + with values above the MPC, nutrient concentrations posed no direct risk for human consumption. However, together with phosphate concentrations (which are up to ten times higher than permissible ecological thresholds), they can cause eutrophication of the aquatic ecosystem. Due to the current flow regime, which has very low discharge rates in the dry season and torrential rainfall and high sediment loads in the wet season, the risk of eutrophication, i.e., excessive concentrations of ammonium and phosphates, is present throughout the year. Accumulation of ammonium and the distribution of nitrate and nitrites in the river water suggest that nitrification is impeded due to a lack of oxygen in both dry and wet seasons. Finally, the investigations show that the risk of water pollution exists and it is necessary to take measures of sanitation and water treatment to prevent the further degradation of water along the Ouémé River.