Hepatitis C virus (HCV) infection has been considered a core reason of chronic liver disorder. Sofosbuvir (SOF) is part of a combined antiviral therapy regimen used to treat chronic HCV infection associated with many side effects. The aim of the study is to demonstrate the effect of SOF and its withdrawal on the submandibular salivary gland as well as on the tongue of adult male albino rats. Thirty adult male albino wistar rats were included in this work. They were randomly split into three groups: group I was the control group. Group II received SOF at a dose of 41 mg/kg once daily orally for four weeks. Group III received SOF as group II and then were kept without treatment for another four weeks. Submandibular glands and tongue samples were processed histologically and immunohistochemically. Morphometrical and statistical studies were implemented. Group II (SOF-treated group) submandibular gland sections revealed marked histological alterations at both ductal and acinar levels. Tongue specimens of this group also showed marked affection of filiform papillae, which was confirmed by scanning electron microscopy. A highly significant rise in the mean area percentage of collagen fibers as well as a highly significant decline in the area percentage of E-cadherin were evident in group II versus the control group at both submandibular glands and tongue specimens. Most changes were ameliorated in the withdrawal group (GIII). In conclusion SOF induces structural changes in submandibular salivary glands and tongue which decreased after its withdrawal.