A novel electrochemical sensor based on ruthenium sulfide nanoparticles decorated activated graphite sheets (RuS2/AG) was designed and fabricated for the determination of antipsychotic drug chlorpromazine hydrochloride (CPZ). Activated graphite sheets (AG) were prepared by non-explosive, non-hazardous and simple chemical activation technique. Then, the AG sheets were used for the synthesis of RuS2/AG nanocomposite by single step hydrothermal synthesis method. The synthesized materials were characterized using field emission scanning electron microscopy (FESEM), transmission electron microscope (TEM), Raman spectrometer, X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). The synergistic effect of the RuS2/AG nanocomposite was applied for the determination of CPZ by cyclic voltammetry (CV) and differential pulse voltammetric (DPV) techniques. Fascinatingly, the RuS2/AG nanocomposite exhibited the excellent electrocatalytic activity and detects the CPZ at very lowest oxidation potential about 0.60 V vs Ag/AgCl in pH-7 PB solution. Moreover, the lowest LOD 8 nM and wider linear ranges from 0.05 to 79.75 and 79.75–1249 μM was obtained towards the CPZ determination. Besides, the proposed sensor shows the good selectivity, satisfactory repeatability, reproducibility and stability. Furthermore, the real time application was evaluated in pharmaceutical tablets and human urine samples.