A highly sensitive nano-materials modified electrode was fabricated for the quantification of Palonosetron Hydrochloride (PAL) using anodic differential pulse voltammetry (A-DPV) for the first time. The synergetic effect of Multi-wall Carbon nano-tubes and nano-zinc oxide particles was utilized for the fabrication of the modified electrode (ZnO-NPs/CNTs/CPE). PAL oxidative degradant was prepared and the degradant's identification and degradation pathway illustration were done by NMR and mass spectrometry. PAL quantification in 0.04M B-R buffer electrolyte solution (PH 7.0) using ZnO-NPs/CNTs/CPE showed peak response with linearity in the concentration range 6.50– 38.50 µM. The peak response showed a remarkable increase in micellar media upon the addition of Sodium Lauryl Sulfate (SLS). The minimum detectability (LOD) of PAL was 1.19 µM and the limit of quantification (LOQ) was 3.61 µM. The validation of the proposed method showed good accuracy, precision, and reproducibility compared to the official method. The approached technique which can be described as an environmentally friendly technique is rapid, sensitive, and inexpensive for PAL determination in the presence of its oxidative degradant, in its pharmaceutical vials, and biological fluids.