Water resources face significant threats from pollutants identified as Persistent Mobile Organic Compounds (PMOCs). These substances are known for their affinity for water, resistance to environmental degradation, and potential adverse effects on human health and the environment, particularly when classified as toxic. Accordingly, a three-year monitoring study (2021-2023) was carried out at a WWTP in Northern Greece (Thessaloniki), utilizing High-Resolution Mass Spectrometry (HRMS) technology to detect (potentially) PMOCs. The monitoring process was based on two basic approaches of HRMS analysis: target and suspect screening. A total number of 2500 different potential PMOCs list was created based on the available literature. Fifty-five of them were identified with the target analysis approach in at least one sample. The results indicated that antihypertensives and beta-blockers were among the most frequently detected PMOCs categories during the sampling period. Specifically, valsartan and irbesartan exhibited substantial increases in concentration, surpassing 5000 ng/L in influent samples and 1000 ng/L in effluent samples. Additionally, the study employed suspect analysis, incorporating potential substances from the literature to enhance the monitoring program. As a result, the list of identified compounds was expanded by 16 additional compounds with a confidence level of 2b identification. This was complemented by retrospective analysis techniques to identify compounds that are challenging to obtain as standard compounds. The study culminated in an estimation of the environmental risks. The findings highlight the ecological risks associated with elevated PMOCs levels and emphasize the need for continuous monitoring and regulatory measures to mitigate potential environmental impacts. Finally, the study contributes to understanding the complex interactions between environmental factors, PMOCs consumption, and pollution in wastewater treatment plants.