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Background: Camostat mesylate, an oral serine protease inhibitor, is a powerful TMPRSS2 inhibitor and has been reported as a possible antiviral treatment against COVID-19. Therefore, we aim to assess the safety and efficacy of camostat mesylate for COVID-19 treatment. Methods: A systematic review and meta-analysis synthesizing randomized controlled trials from PubMed, Scopus, Embase, Cochrane, Web of Science, clinical trials.gov, and medrxiv until June 2023. The outcomes were pooled using Mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. The protocol is registered in PROSPERO with ID CRD42023439633. Results: Nine RCTs, including 1,623 patients, were included in this analysis. There was no difference between camostat mesylate and placebo in producing negative PCR test results at 1–7 days (RR: 0.76, 95% CI: [0.54, 1.06] P = 0.1), 8–14 days (RR: 1.02, 95% CI: [0.84, 1.23] P = 0.87), or 15–21 days (RR: 0.99, 95% CI: [0.82, 1.19] P = 0.90); clinical resolution of symptoms at 1–7 days (RR: 0.94 (95% CI: 0.58, 1.53) P = 0.81), 8–14 days (RR: 0.91, 95% CI: [0.74, 1.11] P = 0.33,), or 15–21 days (RR: 0.77, 95% CI: [0.40, 1.51] P = 0.45); and time to symptom improvement (MD:-0.38 weeks (95% CI: [-1.42, 0.66] P = 0.47, I2 = 85%). Conclusion: Camostat mesylate did not improve clinical outcomes in patients with COVID-19, compared to placebo. [ABSTRACT FROM AUTHOR]