Electrically conductive polymeric nanocomposites with nanoparticles are adaptable types of nanomaterials that are prospective for various applications. The extraordinary features of copper oxide (CuO) and aluminium oxide (AlO) nanostructures, encourages extensive studies to prospect these metal oxide nanocomposites as potential electroactive materials in sensing and biosensing applications. This study suggested a new CuO/AlO nanocomposite-based polymeric coated wire membrane sensor for estimating naltrexone hydrochloride (NTX) in commercial formulations. Naltrexone hydrochloride and sodium tetraphenylborate (Na-TPB) were incorporated in the presence of polymeric polyvinyl chloride (PVC) and solvent mediator -nitrophenyloctyl ether (-NPOE) to form naltrexone tetraphenylborate (NTX-TPB) as an electroactive material. The modified sensor using NTX-TPB-CuO/AlO nanocomposite displayed high selectivity and sensitivity for the discrimination and quantification of NTX with a linearity range 1.0 × 10-1.0 × 10 mol L and a regression equation E = (58.25 ± 0.3) log [NTX] + 754.25. Contrarily, the unmodified coated wire sensor of NTX-TPB exhibited a Nernstian response at 1.0 × 10-1.0 × 10 mol L and a regression equation E = (52.1 ± 0.2) log [NTX] + 406.6. The suggested modified potentiometric system was validated with respect to various criteria using the methodology recommended guidelines.