P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) in the modern era. Clinical trials have shown that it could lower the risk of bleeding complications without increased ischemic events as compared to standard dual antiplatelet therapy (DAPT). However, the efficacy and safety of this novel approach among patients with acute coronary syndrome (ACS) are controversial because they have a much higher risk for recurrent ischemic events. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with ACS. We conducted a meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12-month DAPT in ACS patients who underwent PCI with stent implantation. PubMed, Embase, the Cochrane library database, ClinicalTrials.gov, and other three websites were searched for data from the earliest report to July 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause mortality, myocardial infarction, stent thrombosis, or stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE), defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. Five randomized controlled trials with a total of 21,034 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy as compared with standard DAPT(OR: 0.59, 95% CI: 0.46-0.75, < 0.0001) without increasing the risk of MACCE (OR: 0.98, 95% CI: 0.86-1.13, = 0.82). The NACE was favorable in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.82, 95% CI: 0.73-0.93, = 0.002). Of note, the overall clinical benefit of P2Y12 inhibitor monotherapy was quite different between ticagrelor and clopidogrel. The incidence of NACE was significantly lower in ticagrelor monotherapy as compared with DAPT (OR: 0.79, 95% CI: 0.68-0.91), but not in clopidogrel monotherapy (OR: 1.14, 95% CI: 0.79-1.63). Both clopidogrel and ticagrelor monotherapy showed a similar reduction in bleeding complications (OR: 0.46, 95% CI: 0.22-0.94; OR: 0.60, 95% CI: 0.44-0.83, respectively). Although statistically insignificant, the incidence of MACCE was numerically higher in clopidogrel monotherapy as compared with standard DAPT (OR: 1.50, 95% CI: 0.99-2.28, = 0.06). Based on these findings, P2Y12 inhibitor monotherapy with ticagrelor would be a better choice of medical treatment for ACS patients after PCI with stent implantation in the current era.