Background Omega-3 may alleviate the severity of coronavirus disease 2019 (COVID-19) by reducing the C-reactive protein (CRP) level, a marker for systemic inflammation. Because the scientific evidence indicating such a role is inconsistent, we aimed to evaluate the effect of Omega-3 on CRP change and CRP level in patients with COVID-19. Methods We conducted a comprehensive search on four databases (PubMed, Web of Science, EMBASE, and Scopus). We included all RCTs comparing Omega-3 with a control group regarding their effect on the CRP levels in patients with COVID-19. We used version two of the Cochrane risk of bias assessment tool to appraise the included studies. We extracted data to an online data extraction sheet. The primary outcomes were CRP change from baseline and CRP serum levels. Results We included four randomized controlled trials (RCTs) with 274 patients in this study. The overall effect estimate favored Omega-3 over the control group in terms of CRP change from baseline (mean difference (MD) =− 2.53, 95% confidence interval (CI): − 4.40, − 0.66) and CRP serum levels at the end of the study (MD =− 6.24, 95% CI: − 11.93, − 0.54). Conclusion Omega-3 showed promising effects on systemic inflammation by reducing CRP levels in COVID-19 patients. Based on this finding, we recommend Omega-3 for COVID-19 patients for its anti-inflammatory actions.