Herein, we report a simple non-enzymatic electrochemical sensor for the detection of serotonin (5-HT) in blood serum using ZnO oxide nanoparticles-copper metal-organic framework (MOF) composite on 3D porous nickel foam, namely, ZnO-Cu MOF/NF. The x-ray diffraction analysis reveals the crystalline nature of synthesized Cu MOF and Wurtzite structure of ZnO nanoparticles, whereas SEM characterization confirms the high surface area of the composite nanostructures. Differential pulse voltammetry analysis under optimal conditions yields a wide linear detection range of 1 ng ml−1 to 1 mg ml−1 to 5-HT concentrations and a LOD (signal to noise ratio = 3.3) of 0.49 ng ml−1, which is well below the lowest physiological concentration of 5-HT. The sensitivity of the fabricated sensor is found to be 0.0606 mA ng−1 ml−1.cm2, and it exhibited remarkable selectivity towards serotonin in the presence of various interferants, including dopamine and AA, which coexist in the real biological matrix. Further, successful determination of 5-HT is achieved in the simulated blood serum sample with a good recovery percentage from ∼102.5% to ∼99.25%. The synergistic combination of the excellent electrocatalytic properties and surface area of the constituent nanomaterials proves the overall efficacy of this novel platform and shows immense potential to be used in developing versatile electrochemical sensors. © 2023 IOP Publishing Ltd.