Because of “green chemistry”, environmentally friendly analytical protocols and devices, negligible waste, and nontoxic materials have made clay minerals of considerable interest to the analytical community. Thus, simple, low cost, easily fabricated and highly selective sodium montmorillonite modified carbon past electrode (Na-MMT/CPE) was applied for nano estimation of Etilefrine.HCl (EF.HCl). FTIR spectrum was used to characterize functional groups of the clay. The electrodes were characterized using electrochemical impedance spectra (EIS), scan electron microscopy (SEM) and cyclic voltammetry. Increasing Na-MMT% up to 7%(w/w) decreases markedly charge-transfer resistances of the modified electrode and increases BET surface area. The active surface area of bare and the modified CPEs was calculated using cyclic voltammetry and K4Fe(CN)6 as a redox probe. Langmuir isotherm indicated monolayer adsorption with binding constant (b) of 1.93 × 107 M−1. The equilibrium parameter RL value (< 1.0) indicated that adsorption process was favorable. ΔGo indicates that the interaction involved both physical and chemical adsorption. Adsorptive stripping voltammetric method was applied for determination of EF.HCl in commercial “Effortil tablets”, human serum and urine. Detection limit of 1.27 × 10−9 M was achieved in spiked human serum. The developed method could be applied to assay the drug in plasma real samples.