Many transformation products (TPs) from organic micropollutants are not included in routine environmental monitoring programs due to limited knowledge of their occurrence and fate. An efficient method to identify and prioritize critical compounds in terms of environmental relevance is needed. In this study, we applied a strategic screening approach based on a case-control concept to identify TPs formed along wastewater-impacted rivers. Time-integrated samples were collected over one week at both ends of a river stretch downstream of a wastewater treatment plant (WWTP) outfall and were analyzed by ultrahigh performance liquid chromatography interfaced with quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS/MS). The screening procedure of the high-resolution MS (HRMS) datasets consisted of three major steps: (i) screening for parent compounds (PCs) attenuated along the stretch; (ii) prediction of potential TPs from these PCs; and (iii) screening for TPs from this list with an increasing trend along the stretch. In total, 32 PCs decreased along the investigated river stretches. From these PCs, eight TPs had increasing concentrations along the studied stretches and could be tentatively identified. The identification of one TP (benzamide) was confirmed by its corresponding reference standard, while no standards were available for the remaining TPs.