Choosing an antithrombotic regime in patients with acute coronary syndrome (ACS) and a concomitant indication for anticoagulation is a challenge commonly encountered by clinicians. Our aim in this article is to evaluate the safety and efficacy of triple antithrombotic therapy (TT, anticoagulant plus dual antiplatelet) versus dual antithrombotic therapy [dual therapy (DT), anticoagulant plus single antiplatelet] in patients with ACS. We included all randomized trials comparing the outcomes of single versus dual antiplatelet therapy in patients with ACS on anticoagulants. The primary outcome was major adverse cardiac events (MACE). Other outcomes studied were all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stroke, stent thrombosis (ST), and major bleeding. The Mantel-Haenszel risk ratio (RR) random-effects model was used to summarize data. Six studies, with a total of 11,437 patients, met our selection criteria. With a follow-up duration of 9–14 months, there was no significant difference between DT and TT in terms of MACE [RR 0.96; 95% confidence interval (CI), 0.79–1.17], all-cause mortality (RR 1.00; 95% CI, 0.77–1.29), cardiovascular mortality (RR 1.03; 95% CI, 0.79–1.34), MI (RR 1.14; 95% CI, 0.90–1.45), stroke (RR 0.83; 95% CI, 0.56–1.23), and ST (RR 1.32; 95% CI, 0.87–2.01). Compared with TT, DT was associated with significant reductions in major bleeding 4.1% versus 6.5% (RR 0.61; 95% CI, 0.45–0.81; number needed to treat = 42), clinically significant bleeding 10.5% versus 16.4% (RR 0.62; 95% CI, 0.48–0.80) and intracranial hemorrhage 0.4% versus 0.8% (RR 0.43; 95% CI, 0.24–0.77). In patients on anticoagulant therapy, the strategy of single antiplatelet therapy (DT) confers a benefit of less major bleeding with no difference in MACE, all-cause mortality, cardiovascular mortality, MI, stroke, and ST.