A new chemiluminescence (CL) method was proposed to measure two widely used drugs, including paracetamol (PCM) and vancomycin (VAN). The CL reaction used was the CuS nanoparticles (CuS NPs)-luminol-O2 system. In this system, CuS NPs played the role of catalyst and increased the CL intensity. CuS NPs were easily synthesized by quick-precipitation. CuS NPs were characterized by spectroscopic techniques, and the mean size of NPs was estimated to be about 9 nm. In the developed CL methods, PCM and VAN decreased the CL intensity. In the proposed method, the linear concentration ranges were 4.0 × 10−5–4.0 × 10−4 mol L-1 of PCM and 2.0 × 10−5–6.0 × 10−4 mol L−1 of VAN. The limit of detections were 2.9 × 10-5 mol L-1 and 8.9 × 10-6 mol L-1 for PCM and VAN, respectively. The relative standard deviations (RSD) of the CL method were 2.99 and 4.31 (n = 6) for the determination of 3.0 × 10−4 mol L−1 PCM and VAN, respectively. It was also shown that the CL methods can measure PCM and VAN concentrations in various real samples.