The toxicity of commonly used drugs, such as acetaminophen (ACAP) and its degradation-derived metabolite of 4-aminophenol (4-AP), underscores the need to achieve an effective approach in their simultaneous electrochemical determination. Hence, the present study attempts to introduce an ultra-sensitive disposable electrochemical 4-AP and ACAP sensor based on surface modification of a screen-printed graphite electrode (SPGE) with a combination of MoS2nanosheets and a nickel-based metal organic framework (MoS2/Ni-MOF/SPGE sensor). A simple hydrothermal protocol was implemented to fabricate MoS2/Ni-MOF hybrid nanosheets, which was subsequently tested for properties using valid techniques including X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), Fourier transformed infrared spectroscopy (FTIR), and N2adsorption-desorption isotherm. The 4-AP detection behavior on MoS2/Ni-MOF/SPGE sensor was followed by cyclic voltammetry (CV), chronoamperometry and differential pulse voltammetry (DPV). Our experimental findings on the generated sensor confirmed a broad linear dynamic range (LDR) for 4-AP from 0.1 to 600 μM with a high sensitivity of 0.0666 μA/μM and a low limit of detection (LOD) of 0.04 μM. In addition, an analysis of real specimens such as tap water sample as well as a commercial sample (acetaminophen tablets) illuminated the successful applicability of as-developed sensor in determining ACAP and 4-AP, with an impressive recovery rate.