In Brazil, environmental occurrence of micropollutants, such as pharmaceuticals, is rarely studied, and these compounds are not part of national water quality guidelines. In this study, we evaluated the occurrence of micropollutants in the Paraibuna River, located in the southeast region of Brazil, which is the most populated region of the country. Surface water samples were taken every 3 months for 1.5 years at four different sites downstream the city of Juiz de Fora. A total of 28 compounds were analyzed on an UHPLC-Orbitrap-MS/MS using a direct injection method. Nine substances were found in at least one water sample, with concentrations ranging from 11 to 4471 ng L-1. The micropollutants found in the river were not detected at the reference site upstream of the city, except for caffeine, which was present at low concentrations in the reference site. Additionally, a nontarget screening of the river samples was applied, which resulted in the identification of 116 chemicals, most of which were pharmaceuticals. Concentrations of most of the micropollutants varied with season and correlated significantly with rainfall events, which caused dilution in the river. The highest observed concentrations were for pharmaceuticals used for treating chronic diseases, such as metformin, which is used to treat diabetes, and were among the most consumed in Juiz de Fora during the study period. Moderate ecotoxicological risks were found for metformin, oxazepam, triclosan, and tramadol. Considering the complex mixture of micropollutants in the environment, more knowledge is needed to elucidate their ecological risk in aquatic ecosystems.