<p>The increasing prevalence of polypharmacy in psychiatric treatment necessitates the development of efficient analytical methods capable of simultaneously monitoring multiple drug classes. This study reports the development and evaluation of a reliable ultra-high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of 15 psychotropic drugs, including antidepressants, antipsychotics, anxiolytics, and antiepileptics, in a single analytical run. Developing a unified method for such a broad spectrum of analytes presents a significant challenge because of their varying physicochemical properties. To overcome this, the chromatographic conditions were systematically optimized; a mobile phase consisting of 2&#xa0;mM ammonium formate, 0.2% formic acid in water (pH 4.7), and 90% acetonitrile achieved optimal separation and ionization of all 15 compounds simultaneously. Samples were prepared by simple protein precipitation with acetonitrile, which provided a reliable workflow with excellent reproducibility for the diverse analyte panel. The method was evaluated, including linearity, accuracy, precision, specificity and carryover based on the acceptance criteria of the ICH M10 guideline, demonstrating excellent linearity (R² &gt; 0.99) and high reliability with accuracy (81.68–100.20%) and precision (relative standard deviation &lt; 12.25%) for quality control samples. This method provides a robust and comprehensive approach for distinguishing therapeutic use from misuse in forensic and clinical settings, meeting the need for accurate multidrug screening.</p>