In the present investigation, a new electrochemical sensor based on carbon paste electrode was applied to simultaneous determine the tramadol, olanzapine and acetaminophen for the first time. The CuO/reduced graphene nanoribbons (rGNR) nanocomposites and 1-ethyl 3-methyl imidazolinium chloride as ionic liquid (IL) were employed as modifiers. The electrooxidation of these drugs at the surface of the modified electrode was evaluated using cyclic voltammetry (CV), differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS) and chronoamperometry. Various techniques such as scanning electron microscopy (SEM) with energy dispersive X-Ray analysis (EDX), X-ray diffraction (XRD) and fourier-transform infrared spectroscopy (FTIR), were used to validate the structure of CuO-rGNR nanocomposites. This sensor displayed a superb electro catalytic oxidation activity and good sensitivity. Under optimized conditions, the results showed the linear in the concentration range of 0.08–900 μM and detection limit (LOD) was achieved to be 0.05 μM. The suggested technique was effectively used to the determination of tramadol in pharmaceuticals and human serum samples. For the first time, the present study demonstrated the synthesis and utilization of the porous nanocomposites to make a unique and sensitive electrode and ionic liquid for electrode modification to co-measurement of these drugs.