The main concern upon fabrication of solid contact potentiometric electrodes is the choice of ion sensing membrane. The key principle is to design a sensor having optimum sensitivity and potential stability along with simplicity, reproducibility, and cost effectiveness. Herein, a novel screen-printed potentiometric sensor has been developed for selective and sensitive determination of piroxicam in its pharmaceutical formulation or human plasma. The obstacle was to improve the limit of detection of the proposed sensor to determine the plasma peak concentration of the cited drug. A three-step optimization protocol has been developed. (I) Novel neutral carrier based on Cu(ii) complex of piroxicam was employed as ion sensing membrane with better sensitivity compared to classical ion exchangers. (II) The sensor was fabricated based on molecular imprinted polymer of piroxicam to assure selectivity. Molecular imprinted polymer was synthesized by precipitation polymerization approach and characterized by field-emission scanning electron microscope, Fourier-transform infrared spectroscopy, and Brunauer-Emmett-Teller measurements for surface area analysis. (III) The obstacle of water layer formation was overcomed by comparing the doping effect of multiwalled carbon nanotubes and graphene nanocomposite on the sensors' signal stability. Three screen printed sensors for piroxicam were developed and their electrochemical performance was assessed. Optimum results for piroxicam were obtained with ion sensing membrane of Cu(ii)-piroxicam complex based on molecular imprinting and multiwalled carbon nanotubes. The obtained Nernstian slope was 28.97 mV/decade with linearity range of 9.7 × 10-1 × 10 M and LOD of 5.2 × 10 M. The sensor was successfully applied into spiked human plasma. This would offer an alternative sensing platform for therapeutic monitoring of piroxicam in biological fluids.