Objective <p>This study aimed to assess the potential antifibrotic impact of zinc sulfate in chronic Hepatitis C Virus (HCV) patients receiving direct-acting antiviral therapy.</p> Methods <p>This randomized controlled study included 50 chronic HCV-infected patients with fibrosis stage (F1 &amp; F2). Participants were randomly assigned to two groups: Group 1 (Control group, <i>n</i> = 25) received standard direct-acting antiviral therapy for 3&#xa0;months, while Group 2 (Zinc group, <i>n</i> = 25) received 50&#xa0;mg/day of zinc sulfate in addition to the standard direct-acting antiviral therapy for the same duration. Baseline and 3-month post-intervention assessments included evaluating serum levels of hyaluronic acid, transforming growth factor beta-1, and fibronectin. Furthermore, indices of liver fibrosis, such as the Fibrosis Index based on the 4 factors (FIB-4) and the Aspartate Transaminase-to-Platelet-Ratio Index (APRI), were calculated during these assessments.</p> Results <p>At baseline, the two studied groups had no statistical difference in demographic and laboratory data. After treatment, serum zinc levels significantly increased in the zinc-treated group compared to the control group. Additionally, serum fibronectin and hyaluronic acid levels were significantly reduced in group 2 (zinc group) compared to group 1 (control group). Moreover, zinc group showed lower APRI scores than the control group after a 3-month follow-up period, but there was non-significant difference in FIB-4 scores between the two groups after treatment. Furthermore, total bilirubin levels were reduced after zinc therapy for 3&#xa0;months.</p> Conclusions <p>Administering zinc sulfate could potentially serve as a safe and efficient therapeutic strategy for the management of hepatic fibrosis in individuals with chronic hepatitis C virus.</p> Trial Registration <p>ClinicalTrials.gov identifier: NCT05465434, On 19/7/2022.</p>