Agomelatine, a new type of antidepressant, targets melatonin and 5-HT2C receptors to improve sleep and mood in treating major depressive disorder. Its side effects range from mild ones like dizziness and headaches to more serious concerns such as allergic reactions, hepatotoxicity, and increased suicide risk, requiring close patient monitoring, especially in younger adults. Sexual function and weight are less affected, but potential serotonin syndrome is another risk to watch for. a composite of copper (Cu) nanoparticle-embedded covalent organic framework (Cu@COF) was synthesized with a simple and rapid reduction-based method. Then, the synthesized composite was characterized with scanning electron microscopy, X-ray diffraction, energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, cyclic voltammetry, and electrochemical impedance spectroscopy techniques. Afterward, it was employed as an electrocatalytic modifier for highly sensitive and selective square wave anodic stripping voltammetric determination of agomelatine at ultra-trace levels. The optimization of experimental parameters such as pH, deposition time, deposition potential, and modifier concentration was carried out using a one-factor-at-a-time approach. Under the optimal conditions (pH=2.0, modifier concentration= 2.3 mg/mL, deposition time = 60 s and deposition potential= -0.23 V), the developed electrode exhibited a linear relationship was observed between the anodic peak current of agomelatine and its concentration, spanning two linear ranges: 0.005-0.1 μmol/L and 0.1-0.6μmol/L.The method exhibited a limit of detection (LOD) of 0.002 μmol/L and a limit of quantification (LOQ) of .0034 μmol/L under optimized conditions. The stability, reproducibility, repeatability, interference, and concurrent investigation of agomelatine drugs were conducted, yielding favorable results. Additionally, the proposed method demonstrated high sensitivity and selectivity in the determination of agomelatine in urine, serum, and saliva specimens.