<p>Vortioxetine (VOX) is a multimodal antidepressant commonly used in long-term therapy, making its sensitive detection in biological samples an important analytical task. Electrochemical detection of VOX on disposable carbon electrodes is often hindered by oxidation at relatively positive potentials, which can lead to background currents, co-oxidation, and surface passivation, thereby reducing analytical reliability. Herein, a fluoride-free alkaline hydrothermal route was adopted to convert MoAlB (MAB) into porous, oxygen-terminated MoAl_1−<i>x</i>B (MBene), employed as a functional interfacial modifier on screen-printed electrodes (SPEs). Formation and surface evolution of MBene were confirmed by electron microscopy, XRD, Raman spectroscopy, and XPS. Compared to bare SPE and parent MAB/SPE, MBene/SPE shifted the VOX oxidation response to a lower-potential window centered at 0.70&#xa0;V vs. Ag/AgCl and generated a markedly stronger faradaic signal under near-neutral pH. Mechanistic evidence from open-circuit potential transients, in situ UV–Vis spectroelectrochemistry, pH and kinetic isotope effect studies, and DFT calculations indicates that the O/OH-rich MBene surface promotes adsorption-assisted VOX preconcentration and interfacial charge redistribution, while the conductive Mo–B framework facilitates charge transfer. Under optimized DPV conditions, the sensor exhibits two linear ranges (0.001–0.090 µM and 0.13–3.80 µM) due to surface-site saturation and diffusion contributions, with high sensitivity evidenced by a 1.0 nM detection limit, repeatability of 0.80% RSD (<i>n</i> = 8), and fabrication reproducibility of 2.9% RSD (<i>n</i> = 5). The platform also demonstrates selectivity against structurally related antidepressants and representative urine interferents, with recoveries of 96.7–109.1% in PBS-diluted urine using a portable potentiostat.</p> Graphical Abstract <p></p>