Background: Silver nanoparticles synthesis is now widely applicable as a method for sensitive spectrophotometric determination of many pharmaceuticals. Objective: A highly sensitive, cheap, green, nonextractive, and accurate spectrophotometric method was developed for the determination of three important antiviral drugs. Methods: The method depends on the formation of silver nanoparticles as a result of the redox reaction between antiviral drugs as a reducing agent and AgNO3 as an oxidizing agent in presence of polyvinyl pyrrolidone as a stabilizing agent. The UV absorbance of the resulted golden yellow silver nanoparticles can be easily measured at 421 nm for Sofosbuvir (SFS) and Ritonavir (RIT) and at 425 nm for Lamivudine (LAM). Results: The LODs were 23.5, 30, and 21.5 nm/mL for SFS, LAM, and RIT, respectively. The LOQs were 70.5, 90, and 64.6 nm/mL for SFS, LAM, and RIT, respectively. The method was validated according to International Conference on Harmonization guidelines, and it was successively applied for the determination of the studied drugs in their different pharmaceutical dosage forms and gave excellent percent of recovery. The results showed excellent agreement with the reported method with respect to precision and accuracy. Conclusions: Being simple, fast, robust, and economic, this method is eligible for use in the routine work in pharmaceutical quality control laboratories. Highlights: A sensitive and economic spectrophotometric method was developed and validated for quantitative determination of SFS, LAM, and RIT. The method was validated and applied for determination of the studied drugs in their different formulations. The method used water as the main solvent, so our proposed method is considered environmentally friendly.