<p>The increasing global consumption of pharmaceuticals and illicit drugs, particularly new psychoactive substances, has resulted in their continuous release into aquatic environments, raising concerns regarding potential adverse effects on ecosystems and human health. In this study, a dispersive micro-solid-phase extraction using customized extraction devices was developed in combination with liquid chromatography–high-resolution mass spectrometry for target and suspect screening, followed by sensitive quantification by liquid chromatography–tandem mass spectrometry. The extraction procedure was optimized using experimental design. Optimal conditions comprised 50&#xa0;mg of Oasis MCX sorbent, 100&#xa0;mL of sample (pH 2, containing 7.5% NaCl, w v⁻¹), and an extraction time of 30&#xa0;min. Under these conditions, limits of quantification ranged from 4.67 to 29.3&#xa0;ng L⁻¹, and extraction recoveries varied between 73.0% and 108% for most target analytes. Application to real wastewater samples included an initial suspect screening step by liquid chromatography–high resolution mass spectrometry using data-dependent acquisition and an untargeted data-mining workflow. The screening results revealed a broad range of compounds, including central nervous system stimulants, cardiovascular drugs, opioid analgesics, and sedatives. Quantification of selected target analytes was subsequently performed by liquid chromatography–tandem mass spectrometry. Among the investigated illicit drugs, THC and cocaine were the predominant compounds detected, whereas fentanyl was present at trace levels (6.17–14.4&#xa0;ng L⁻¹). The proposed workflow enables robust, sensitive monitoring of illicit drugs and pharmaceuticals in wastewater for epidemiological and environmental surveillance applications.</p> Graphical abstract <p></p>