In this study, we have constructed a novel voltammetric sensor based on montmorillonite clay (MMT) incorporated with CeO2 nanoparticles using a composite graphite paste electrode as a cross linker (MMT-CeO2NPs /GPG-PE) for the trace determination of tadalafil (TAD) drug. The characterization of CeO2 nanoparticles has been conducted using various analytical techniques, including XRD, TEM, and HR-TEM. The morphology of the composite of CPG and MMT-CeO2NPs/CPG was elucidated through scanning electron microscopy (SEM). The newly developed sensor (MMT-CeO2NPs/CPG-PE) exhibited remarkable efficiency towards TAD oxidation using adsorptive stripping square-wave voltammetry (AdS-SWV) in Mcllvaine buffer solution (pH 8.0). A highly selective and sensitive method for TAD detection has been successfully applied based on MMT-CeO2NPs/CPG-PE, showing two different linear concentration ranges of 0.005−0.1 µM and 0.1–9.9 µM. The LOD and LOQ were determined to be 1.97×10−10 M and 6.57×10−10 M respectively, with a sensitivity of 3916 µA µM−1 cm−2. Interestingly, the sensing electrode exhibited excellent reproducibility, reusability, and stability even after 30 days. Moreover, the newly developed nano-sensor (MMT-CeO2NPs/CPG-PE) has been effectively utilized for the accurate detection of TAD in pharmaceutical formulations and spiked human blood serum and urine samples, demonstrating no interference from other substances.