Pharmaceutical residues have become micropollutants of emerging concern in wastewater. Insufficient removal by wastewater treatment plants (WWTPs) can result in negative ecotoxicological impacts on aquatic ecosystems. Therefore, the EU Urban Wastewater Treatment Directive (UWWTD 2024/3019) requires quaternary treatment upgrades and regular monitoring in European wastewater treatment plants. This necessitates efficient and easy-to-implement wastewater analysis methods. Consequently, this study presents a novel, sensitive, and reliable HRMS-based method for the simultaneous determination of twelve indicator substances (nine UWWTD-listed and three substitutes) in WWTP influent and effluent. The method is based on solid-phase extraction (SPE) of 2 mL wastewater samples, followed by reversed-phase ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) employing an Orbitrap Exploris™ 240. Detection was carried out using heated electrospray ionisation in positive ionisation mode (HESI+), except for diclofenac (HESI-). Quantification was performed using highly sensitive SIM scans, while high-resolution full-scan spectra were acquired for confirmation. Limits of quantification (LOQ) ranged mostly between 15 and 30 ng/L, except for candesartan, irbesartan, and diclofenac with LOQ > 50 ng/L. A laboratory validation demonstrated high precision and accuracy for all selected pharmaceuticals. Furthermore, the method was successfully applied to raw and treated wastewater from wastewater treatment plants (WWTPs) in the Saxon-Czech border region, which differ in terms of wastewater throughput and population equivalents. As a result, this method offers a rapid quantification approach for assessing the removal efficiency of pharmaceuticals and potential substitutes categorised in the UWWTD.