The advanced and highly functional properties of Al2O3 and NiO nanoparticles promote the widespread use of metal oxides as remarkable electroactive materials for sensing and electrochemical applications. The proposed study describes a comparison of the sensitivity and selectivity of two modified wire membrane sensors enriched with Al2O3 and NiO nanoparticles with conventional wire membranes for the quantification of the antidiabetic drug metformin hydrochloride (MTF). The results show linear relationships of the enriched Al2O3 and NiO nanosensors over the concentration ranges 1.0 × 10−10–1.0 × 10−2 mol L−1 and 1.0 × 10−6–1.0 × 10−2 M for both the modified sensors and the conventional coated wire membrane sensors. The regression equations were EmV = (52.1 ± 0.5) log (MTF) + 729 for enriched nanometallic oxides, EmV = (57.04 ± 0.4) log (MTF) + 890.66, and EmV = (58.27 ± 0.7) log (MTF) + 843.27 with correlation coefficients of 0.9991, 0.9997, and 0.9998 for the aforementioned sensors, respectively. The proposed method was fully validated with respect to the recommendations of the International Union of Pure and Applied Chemistry (IUPAC). The newly functionalized sensors have been successfully used for the determination of MTF in its commercial products.