Background: Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19. Methods: A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI). Results: The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir–daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22). Conclusion: Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.