Derivative spectrophotometry, which is primarily based on the first and second derivative spectra of absorption, was applied for individual and simultaneous spectrophotometric determination of diclofenac sodium (DS) and nicotinamide (NAM) in the ultraviolet region. The method depends on 1st and 2nd derivative UV spectrophotometry, with the amplitude of peak-to-base line, peak to peak, the area under peak at selected spectrum intervals and zero-crossing at certain wavelengths for each compound measurement. Under optimal conditions, a linear working range of 5-80 μg.ml -1 and 10-140 μg.ml -1 for (DS) and (NAM) with correlation coefficient R 2 between 0.9938-0.9998. The mean % recoveries were found to be in the range of 97.95-102.50 % for two drugs. The proposed technique has been effectively applied to the estimation of (DS) and (NAM) in pharmaceutical formulations.