In the present work, a green method improved by surface response methodology (SRM) has been used for the synthesis of zinc oxide nanoparticles (ZnONPs) from coffee husks extract, in which Santa Barbara‐15 (SBA‐15) mesoporous silica has been embedded. The composite formed has been drop coated on bare glassy carbon electrode and the resulting sensor (ZnONPs/SBA‐15/GCE) was used for the sensing of acetaminophen (ACT). Reaction factors such as pH, incubation time and precursor concentration were optimized during nanoparticles synthesis using SRM. The synthesized nanoparticles and the composite were characterized by ultraviolet‐visible spectrophotometry (UV‐Vis), Fourier transform infrared (FTIR) spectroscopy, powder X‐ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X‐ray (EDX/EDX‐mapping) analysis, thermogravimetry analysis/differential thermogravimetry (TGA/DTG), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS), showing the good elaboration of ZnONPs/SBA‐15/GCE. After optimization of parameters susceptible to affect the detection limit of ACT, the calibration curve was plotted from 4 μM to 32 μM, showing good linear response with a detection limit of 0.11 μM. The developed sensor shows good sensitivity, reproducibility, repeatability and storage stability at room temperature and was successfully applied for the determination of ACT in pharmaceutical sample.