A highly ultrasensitive sensor that relied on Cr/ZnO-NPs was developed to detect etilefrine hydrochloride (ETF) in different matrices via a particular green voltammetric technique. The X-ray diffraction pattern showed the nanomaterials of the polycrystalline hexagonal structure. The energy-dispersive X-ray spectrum approved the presence of Cr 3+ inside the host zinc oxide framework. The morphological and topological characteristics were visualized using transmission electron microscopy and atomic force microscopy micrographs describing the nanoparticles in spherical-like shape with large-surface area. The energy gap (E g ) was evaluated from transmittance (T %) and reflectance (R %) spectra within the visible region. The optimization study indicated that the Cr/ZnO-NP/CPE sensor has high sensitivity, thanks to the distinctive physical and chemical properties of the fabricated electrode. A new approach showed a great selectivity for determining ETF in different matrices in the presence of other interferents like levodopa. Under optimal circumstances, the squarewave voltammetry revealed a linear response to ETF from 0.01 to 10 μmol L −1 (r = 0.9996) with quantification and detection limits of 9.11 and 2.97 nmol L −1 , respectively. Finally, the proposed approach was effectively applied to estimate ETF in pharmaceutical dosage forms and biological fluids using simple, accurate, and selective electrochemical electrode. The greenness profile assessment of the developed method was performed using the Eco-Scale and green analytical procedure index. These tools indicated that the proposed method is an eco-friendly technique for the determination of ETF in different matrices.