The concern on the fate and distribution of contaminants of emerging concern (CECs) is a burning topic due to their widespread occurrence and potential harmful effects. Particularly, antibiotics have received great attention due to their implications in antimicrobial resistance occurrence. The impact of wastewater treatment plants (WWTP) is remarkable, being one of the main pathways for the introduction of CECs into aquatic systems. The combination of novel analytical methodologies and risk assessment strategies is a promising tool to find out environmentally relevant compounds posing major concerns in freshwater ecosystems impacted by those wastewater effluents. Within this context, a multi-target approach was applied in three Spanish river basins affected by different WWTP treated effluents for spatio-temporal monitoring of their chemical status. Solid phase extraction followed by ultra-high-performance liquid chromatography were used for the quantification of a large panel of compounds (n = 270), including pharmaceuticals and other consumer products, pesticides and industrial chemicals. To this end, water samples were collected in four sampling campaigns at three locations in each basin: (i) upstream from the WWTPs; (ii) WWTP effluent discharge points (effluent outfall); and (iii) downstream from the WWTPs (500 m downriver from the effluent outfall). Likewise, 24-h composite effluent samples from each of the WWTPs were provided in all sampling periods. First the occurrence and distribution of these compounds were assessed. Diverse seasonal trends were observed depending on the group of emerging compounds, though COVID-19 outbreak affected variations of certain pharmaceuticals. Detection frequencies and concentrations in effluents generally exceeded those in river samples and concentrations measured upstream WWTPs were generally low or non-quantifiable. Finally, risks associated with maximum contamination levels were evaluated using two different approaches to account for antibiotic resistance selection as well. From all studied compounds, 89 evidenced environmental risk on at least one occasion in this study.