The Integrated Water Resources Management regulations aim to ensure a good status of surface water quality and its sustainable use. Water quality monitoring of various water users supports the identification of pollution sources and their environmental impacts. The priority pollutants generated by wastewater discharges from municipal, industrial wastewater treatment plants or agricultural areas are of great interest due to their eco-toxicological effects and bio-accumulative properties. The aim of this study was to monitor the priority organic and inorganic pollutants from the Siret River basin, in Romania, with the purpose of assessing the surface water quality status and evaluating it by the Water Quality Index (WAWQI) method. The monitoring of inorganic priority pollutants (e.g., As, Cd, Hg, Ni, Pb) and organic priority pollutants (e.g., Naphthalene, Anthracene, Phenanthrene, Fluoranthene, Benzo(a)anthracene, Benzo(b)fluoranthene, Benzo(k)fluoranthene, Benzo(a)pyrene, Benzo(ghi)perylene, Indeno(1,2,3-cd)pyrene, α, β, and γ-Hexachlorocyclohexane, and Di-2-ethyl-hexyl-phthalate) was conducted within the Siret River basin, during the period 2015–2020. With this purpose, 21 sampling points (18 river sections and 3 lakes) were considered to assess the water quality. The results of this study proved that the water quality within the Siret River basin is generally classified in the 2nd or 3rd class. The spatial distribution of the water quality index values, using ARCGIS, also highlighted the fact that the water quality is mostly unsuitable for drinking water supplies, being influenced by the quality of its main tributaries, as well as by the effluent of wastewater treatment plants.