Exploring the contamination profile of multi-class emerging contaminants (ECs) in wastewater is highly desirable. To this end, the occurrence, removal, mass loading and risks associated with a large panel of pharmaceuticals and personal care products, illicit drugs, perfluorinated compounds and organophosphate flame retardants in two wastewater treatment plants (WWTPs) in the region of Thessaloniki (Greece) after a survey is illustrated. Influent and effluent wastewaters were submitted to solid phase extraction on Oasis HLB cartridges, followed by ultra-high-performance liquid chromatography Orbitrap high-resolution mass spectrometry (UHPLC–Orbitrap MS). Influent concentrations in both WWTPs were notably higher than effluent, with caffeine, acetaminophen, irbesartan and valsartan being the most ubiquitous compounds, exhibiting elevated concentrations. Average effluent concentrations ranged from below the method quantification limits (<MQL) to remarkably high values (μg L−1 scale), such as for caffeine, acetaminophen, diclofenac, irbesartan and valsartan, among others. Removal efficiencies ranged between −273% for lamotrigine and 100%, i.e., for the UV filter BP1. Notably, the polar compounds such as cytarabine, methotrexate and capecitabine were removed at a rate >80% in both WWTPs, allowing the correlation between logKow and removals. Interesting trends for the illicit drugs were revealed by means of mass loading estimation, as in the case of benzoylecgonine (71.6 mg/day/1000 inhabitants). Ecotoxicological risk assessment was evaluated for both single components and mixture, using three approaches: risk quotient (RQ), risk quotient considering frequency (RQf) and toxic units (TU). Irbesartan and telmisartan posed a high risk in all trophic levels, while fish was the most sensitive taxa for diclofenac. This work aspires to intensify the surveillance programs for the receiving water bodies, as well as to motivate the investigation of toxicity to non-target organisms. Display omitted •172 multi-class emerging contaminants were monitored in two Greek municipal WWTPs.•80 compounds (46% of the method's total scope) were detected at least in one sample.•12% and 33% of the identified target ECs were eliminated in each WWTP, respectively.•Risk assessment was performed for both individual ECs and observed mixtures.•Optimized RQf, considering mean concentration and detection frequency was employed.