A comprehensive meta-analysis was performed to investigate whether the combination of high-/low-dose of aspirin and various intensities of warfarin (W) offer greater benefit than aspirin (ASA) alone. A total of 14 randomized clinical trials (RCTs) having 26,916 patients with acute coronary syndrome (ACS) met inclusion criteria. The efficacy and safety of all outcomes which included myocardial infarction (MI), all-cause death, stroke, and bleeding were calculated. The overall outcomes analysis showed there was no significant difference in the risk of MI (relative ratio [RR] 0.959, 95 % confidence interval [CI] 0.78–1.04, P = 0.308), stroke (RR 0.789, 95 % CI 0.57–1.09, P = 0.145), and all-cause death (RR 1.007, 95 % CI 0.93–1.09, P = 0.87) between the combination group and ASA group. The subgroup analysis suggested that ASA (≤100 mg/day) plus W (mean international normalized ratio [INR] 2.0–3.0) decreased the risk rate of stroke (RR 0.660, 95 % CI 0.50–0.87, P = 0.003). There was a lower risk of MI (RR 0.605, 95 % CI 0.47–0.77, P < 0.0001) as well as stroke (RR 0.594, 95 % CI 0.45–0.79, P < 0.0001) between W (INR 2.0–3.0) combined with ASA (mean dose ≥100 mg/day) and ASA. However, the risk of major bleeding (RR 1.738, 95 % CI 1.45–2.08, P < 0.0001) and minor bleeding (RR 2.767, 95 % CI 2.12–3.61, P < 0.0001) was almost doubled in the combined groups. Compared with ASA, high-dose aspirin with moderate-intensity warfarin (INR 2.0–3.0) may better reduce the risk of MI and stroke but confer an increased risk of bleeding.