Transferrin (TRF) is a type of glycoprotein present in blood plasma that plays a vital role in facilitating the absorption, storage, and movement of iron(III) ions within the circulatory system of multiple vertebrates. Herein, we report one-pot solvothermal synthesis of Copper Metal-Organic Framework nanosheets modified nickel foam (Cu-MOF/NF) for electrochemical detection of transferrin (TRF) in simulated human blood serum. The crystal structure of the Cu-MOF nanosheets was determined through X-ray diffraction (XRD), while Raman spectroscopy and Fourier-transform infrared spectroscopy (FTIR) analysis were employed to investigate the vibrational modes and the presence of surface OH groups, respectively. The nanosheet morphology of the Cu-MOF was observed and characterized using scanning electron microscopy (SEM) micrographs.The as-fabricated Cu-MOF/NF exhibits a sensitivity of 1.36 mA/x (x = mg.mL⁻¹cm⁻²) for a linear range of concentrations from 1 mg mL⁻¹ – 100 mg mL⁻¹ with a low limit of detection (LOD) of 0.81 mg mL⁻¹. The sensor exhibited good selectivity for TRF, even in the presence of interfering ions such as bovine serum albumin, ascorbic acid, uric acid, and urea, with concentrations 100-fold higher than TRF. The porous nickel foam with high conductivity, offers numerous active sites and pathways for ion transport, as well as pathways for electron transport during electrochemical catalytic reactions. This performance of the sensor is attributed to Cu ²⁺/Cu⁺ redox couple at the octahedral sites of the Cu-MOF facilitating the electro-oxidation of TRF and charge-carrier delocalization during the catalytic reaction. The as-fabricated sensor is successful in the determination of trace level TRF concentration the human blood serum with excellent recovery percentages of 108.33% This proves Cu-MOF/NF as a promising platform for various electrochemical analytical applications.