The present manuscript describes simple, sensitive, rapid, accurate, precise and economical derivative spectroscopic method for the simultaneous determination of tolperisone hydrochloride (TOL) and diclofenac sodium (DIC) in bulk and synthetic mixture. Derivative spectroscopy offers a useful approach for the analysis of drugs in mixtures. In this study a first-derivative spectroscopic method was used for simultaneous determination of tolperisone hydrochloride and diclofenac sodium using the zero-crossing technique. The measurements were carried out at wavelengths of 250.60 and 311.20nm for tolperisone hydrochloride and diclofenac sodium respectively. The method was found to be linear (r2>0.9970) in the range of 5- 40 μg/ml for tolperisone hydrochloride at 250.60 nm. The linear correlation was obtained (r2>0.9990) in the range of 5-50 μg/ml for diclofenac sodium at 311.20 nm. The limit of determination was 0.65 and 0.55 μg/ml for tolperisone hydrochloride and diclofenac sodium respectively. The limit of quantification was 2.01 and 1.67 μg/ml. The method was successfully applied for simultaneous determination of tolperisone hydrochloride and diclofenac sodium in binary mixture.