Abstract Background: Sofosbuvir is a nucleotide analog that has activity against all hepatitis c virus genotypes. Aim of work:The aim of this study was to demonstrate the effect of Sofosbuvir on the cornea of adult male albino rat. Materials and methods: Thirty-five adult male albino rats were used in this experiment. Animals were divided into three groups; Group I control (negative and positive), Group II received Sofosbuvir orally by gastric tube at a dose of 4mg/kg per day for 5 weeks. Group III (Sovaldi and Chrysin treated), received SOV as in group II and Chrysin was given orally by a gastric tube, at a dose of 50 mg/kg once daily for 60 days. All rats were examined for histological study using Hematoxylin and Eosin and Mallory trichrome stains. Immunohistochemical expression for E-cadherin and Caspases-3 was performed. Morphometric and statistical analysis were also performed. Results: Examination of H&E stained sections of Sovaldi- treated cornea showed irregular upper free surface together with desquamation of surface epithelial cells. Bowman’s layer was interrupted and separated. Stroma showed irregularly arranged collagen fibers and separated by wide spaces. Mallory trichrome stained- sections revealed disorganized collagen fibers. Immunohistochemically there was decrease of E-Cadherin expression and dramatically up-regulated expression of Caspases. Conclusion: Sofosbuvir have detrimental histological and immunohistochemical changes in cornea and Chrysin attenuate these changes.