We modified the surface of carbon paste electrode (CPE) with octahedral palladium (Pd²⁺)-doped cobaltite (Co₃O₄) composite (Oh-Pd²⁺:Co₃O₄–C/CPE) as a novel voltammetric sensor to simultaneously detect amitriptyline and venlafaxine. The techniques of differential pulse voltammetry, electrochemical impedance spectroscopy, chronoamperometry and cyclic voltammetry were employed to determine the electrochemical responses of these analytes. The findings highlighted the ability of as-fabricated sensor to facilitate the amitriptyline and venlafaxine oxidation. Peak currents for both analytes differed linearly with their concentrations (between 1.0 × 10⁻⁸ M to 9.0 × 10⁻⁴ M) for the analytical performance of the sensor. The limit of detection calculated by differential pulse voltammetry was 2.31 nM for amitriptyline and 3.56 nM for venlafaxine. We found several advantages for the modified electrode, including a simple preparation method, impressive sensitivity, admirable repeatability, and narrow detection limitations. The proposed sensor was able to detect amitriptyline and venlafaxine in real drug, serum and urine specimens.