<p>Therapeutic monitoring of agomelatine (AG), an antidepressant with significant pharmacokinetic variability, is hindered by the complexity and cost of conventional methods. This work presents a novel electrochemical sensor employing a ternary FeZn-layered double hydroxide (LDH)/graphene/polyaniline nanocomposite for sensitive AG detection in biological and pharmaceutical samples. The synergistic properties of the nanocomposite—combining catalytic activity, high conductivity, and electrochemical stability—were confirmed through XRD, FESEM-EDS, and XPS characterization. Electrochemical analysis showed a 65% reduction in charge transfer resistance and a 21-fold increase in electroactive surface area (0.576 cm²) compared with unmodified electrodes. Using square-wave voltammetry, the sensor achieved a broad linear detection range (5–140&#xa0;nM), high sensitivity (950.7 nA nM⁻¹&#xa0;cm⁻²), and a low detection limit. It demonstrated excellent reproducibility (&lt; 2.5% RSD) and high recoveries (96.9–102.9%) in human urine and commercial tablets, surpassing existing nanocomposite sensors. The sensor maintained performance against 100-fold excesses of common interferents (e.g., glucose, ascorbic acid, Na⁺, Ca²⁺). By overcoming key limitations in plasma compatibility and sensitivity, this FeZn LDH/graphene/polyaniline sensor offers a robust, sustainable platform for real-time AG monitoring, directly applicable in clinical diagnostics and pharmaceutical quality control.</p> Graphical Abstract <p></p>