BackgroundIt remains controversial whether adding ezetimibe to low/moderate‐intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high‐intensity statin regimens.HypothesisA combination of low/moderate‐intensity statins plus ezetimibe might be more effective and safer than high‐intensity statin monotherapy.MethodsWe searched databases for randomized controlled trials comparing lipid profile alterations, drug‐related adverse events, and MACE components between high‐intensity statin monotherapy and low/moderate‐intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random‐effects model.ResultsOur comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low‐density lipoprotein cholesterol (LDL‐C) levels compared to monotherapy (MD = −6.6, 95% CI: −10.6 to −2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13–0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51–0.74). The occurrence of MACE was similar between the two treatment groups.ConclusionsAdding ezetimibe to low/moderate‐intensity statins resulted in a greater reduction in LDL‐C levels, a lower rate of myalgia, and less drug discontinuation compared to high‐intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta‐analysis, the observed reduction in LDL‐C levels in the combination group did not correlate with a reduction in MACE compared to the high‐intensity statin group.