The advanced and high-functional activities of magnesium oxide and copper oxide nanoparticles encourage the extensive use of these metal oxides as remarkable electroactive materials in electrochemical and sensing detections. The current study described a comparative sensing activity and selectivity of modified coated wire membrane sensors enriched with magnesium oxide and copper oxide nanoparticles for quantifying the breast cancer medication letrozole (LTZ) in its pharmaceutical form and human plasma. The fabricated sensors were based on the incorporation of LTZ with phosphomolybdic acid (PMA) to form the electroactive complex letrozole-phosphomolybate (LTZ-PM) in the presence of -nitrophenyloctyl ether (-NPOE) as a solvent mediator. Under optimum conditions, the modified sensors LTZ-PM-MgONPs and LTZ-PM-CuONPs demonstrated linear relationships of 1.0 × 10-1.0 × 10 and 1.0 × 10-1.0 × 10 mol L, respectively. Least square equations were calculated as E = (56.4 ± 0.7) log [LTZ] + 569.6 and E = (58.7 ± 0.3) log [LTZ] + 692.6 for LTZ-PM-MgONPs and LTZ-PM-CuONPs, respectively. The conventional type LTZ-PM showed a potential response E = (53.3 ± 0.5) log [LTZ] + 451.4 over concentration range of 1.0 × 10-1.0 × 10 mol L. The suggested sensors were successfully used to determine LTZ in pharmaceutical formulations and biosamples. Method validation ensured the suitability of the suggested potentiometric sensors.