In the realm of electrochemical sensor application, the development and fabrication of semiconducting metal oxides with the integration of conducting polymers for the trace-level detection of pharmaceutical medicines garnered considerable interest. Herein, we reported facile cadmium oxide decorated with polypyrrole nanotubes fabricated on a glassy carbon electrode (CdO@PPy/GCE) for efficient determination of antihistamine drug promethazine hydrochloride (PMH). The as-synthesized CdO@PPy composite was characterized by various analytical tools like X-ray powder diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. Furthermore, the electrocatalytic activity of the modified electrode for PMH detection was examined by voltammetry and amperometric methods, and the modified electrode exhibited lower charge transfer resistance compared to the bare GCE. Under the optimized condition, the fabricated electrode shows a wide linear range (50−550 μM), better sensitivity (0.13 μAμM −1 cm −2 ), low detection limit (10.83 nM) (S/N = 3), and excellent selectivity and reproducibility toward PMH detection. Moreover, the modified GCE depicted eminent practical ability for PMH detection in lake water and pharmaceutical tablets.