In this study, rapid resonance Rayleigh scattering (RRS), spectrophotometric, and spectrofluorimetric methods were performed for facile quantitation of daclatasvir dihydrochloride without interference from sofosbuvir (a co‐formulated anti‐hepatitis C virus drug). The proposed approaches were based on forming a binary complex between daclatasvir dihydrochloride and merbromin reagent at pH 4.1. The binary complex was measured spectrophotometrically at λmax = 544 nm. The spectrofluorimetric approach relied on the quenching effect of daclatasvir dihydrochloride on the fluorescence strength of merbromin at λEmission = 545 nm. The RRS approach depended on augmentation in the merbromin RRS spectrum at 363 nm upon addition of daclatasvir dihydrochloride. The presented methodologies were linear over the concentration ranges 2.5−15.0, 0.2−1.6 and 0.15−3.0 μg ml−1 with detection limits of 0.45, 0.046, and 0.036 μg ml−1 for the spectrophotometric approach, the spectrofluorometric approach, and RRS approach, respectively. Current approaches were validated in compliance with International Council for Harmonisation guidelines and utilized practically to estimate daclatasvir dihydrochloride either in binary mixtures with sofosbuvir or in its commercial tablet dosage form with good results. Moreover, the test for content uniformity was applied successfully on commercial tablets using the current spectroscopic approaches.