Role of omega-3-Fatty acids, especially eicosapentaenoic acid (EPA), in reducing cardiovascular events is not clear. We conducted a meta-analysis including trial sequential analysis (TSA) of all available randomized controlled trials (RCTs) assessing the impact of EPA + statin on cardiovascular risk reduction. The aim is to appraise cardiovascular risk reduction with EPA and statin taken together. A comprehensive search of PubMed and EMBASE databases was conducted for all RCTs that compared EPA + Statin versus statin alone and included outcomes related to cardiovascular health. We calculated a comprehensive odds ratio (ORs) and 95% confidence intervals (CIs) using a random-effects model. We included 5 RCTs totaling 27,415 patients. Our results demonstrated that EPA + statin resulted in 18% reduction in the incidence of MACE (OR = 0.78; 95% CI: 0.65 to 0.93, I² = 54%, p value <0.01) and 30% reduction in myocardial infarction (MI) (OR = 0.71; 95% CI: 0.61 to 0.82, I² = 0% p value <0.01) as compared with statin alone. With respect to MACE, the number needed to treat was 49. The statistical significance for reduction in the incidence of MACE with EPA+ statin was further augmented with trial sequential analysis. However, combined therapy of EPA + statin demonstrated no significant association on incidence of stroke when compared with statin alone or all-cause mortality. In conclusion, this meta-analysis demonstrated that EPA significantly reduced the incidence of MACE when combined with statin therapy, which is mainly driven by a significant reduction in myocardial infarction.