AbstractA two‐step experimental design was followed to develop a potentiometric solid contact ion‐selective electrode for sertaconazole (STN) determination. A full factorial design was first employed in screening for the best cation exchanger, ionophore and conducting polymer. Amounts of the selected cation exchanger; tetrakis[3,5‐bis(trifluoromethyl)phenyl] borate (TFPB), and ionophore; calix[6]arene (CX6), incorporated in STN sensing membrane were then optimized with the aid of face centered composite design. Calibration slope, detection limit and electrode selectivity in presence of another imidazole‐classified drug; econazole, were the selected responses in both designs. The optimized ion‐sensing membrane, containing 1.0 mg TFPB and 9.9 mg CX6, showed enhanced responses compared to the primarily screened ones. This optimized electrode exhibited a linear response over a concentration range of 1.0×10−6‐−1.0×10−3 M with a Nernstian slope of 57.50 mV/decade. The detection limit was lowered by about one order of magnitude via this optimization to equal 3.16×10−7 M. The proposed electrode was successfully challenged for STN determination in the presence of other imidazoles. It was then used for STN determination in cream and spiked plasma as an example of biological fluid. Our proposed potentiometric method was finally compared to the reported chromatographic ones in terms of sensitivity, and greenness evaluation by the widely applicable Analytical GREEnness (AGREE) tool. The comparison revealed the superiority of our method in terms of sensitivity and sustainability.