Abstract Background The combination of daclatasvir (DCV) and sofosbuvir (SFV) is now widely used as an ideal treatment for hepatitis C virus (HCV) infection. For this purpose, simple, sensitive, rapid, and smart spectrophotometric methods were developed and validated for the determination of these drugs in their combined dosage form. Objective Development of smart, sensitive, low-cost spectrophotometric methods for the determination of DCV and SFV in their combined dosage form. Methods Ratio subtraction (RS), amplitude modulation (AM), and mean-centering spectrophotometric methods were established and validated for the estimation of SFV in the presence of DCV without previous separation, using a unified regression equation. Results A linearity range of 2.5–25.0 µg/mL was confirmed for the direct measurement of DCV at 316 nm (because there is no interference from SFV. Linearity was confirmed over a concentration range of 10.0–80.0 µg/mL for SFV. The current methods were established according to the ICH recommendations, and specificity was examined by testing synthetic mixtures of both drugs. They were tested on their tablet dosage form, and a good recovery was obtained. Conclusion The current methods proved to be simple, specific, and economical. A statistical study of the current ratio approaches and published methods showed there was no apparent statistical variation. Highlights Both antiviral agents can be quantified in the presence of each other by the current methods, which is a significant time- and cost-saving benefit of the developed methods. This benefit is even more important in the case of the combined dosage form (Darvoni® tablets) for the pharmaceutical market.