The discovery of new direct-acting antiviral drugs gave rise to a leap forward in the treatment of hepatitis C viral infections. For the first time since 1998, the Food and Drug Administration (FDA) approved interferon-free oral treatment paradigms. Among the new treatment regimens, the combinations of sofosbuvir/daclatasvir and sofosbuvir/velpatasvir became ideal treatment regimens for being potent, highly tolerated, and used once daily. For that purpose, a new sensitive high-performance thin-layer chromatography (HPTLC) method was developed and validated for the simultaneous determination of sofosbuvir and velpatasvir. The proposed method used Merck HPTLC silica gel 60 F254 aluminum plates as the stationary phase. The mobile phase was a combination of methylene chloride‒methanol‒ethyl acetate‒ammonia (25%) at a ratio of 5:1:3:1 (v/v). The calibration curves were linear over a wide range of 100–2000 ng per spot for the studied drugs. The limits of detection were 30.02 and 27.60 ng per spot, and the limits of quantification were 90.06 and 82.80 ng per spot for sofosbuvir and velpatasvir, respectively. The suggested method was successfully applied for analysis of the studied drugs in their pharmaceutical dosage forms, and excellent recovery results were obtained. Being simple, fast, robust, and economic, this method is eligible for use in the routine work in pharmaceutical quality control laboratories