Clinical practice guidelines from the American Heart Association recommend consideration of prophylactic anticoagulation to prevent left ventricular thrombus (LVT) formation in patients with anterior ST-elevation myocardial infarction. These guidelines were given a low certainty of evidence (class IIb, level C), relying primarily on case studies and expert consensus to inform practice. Our objective was to compare the safety and efficacy of prophylactic anticoagulation, in addition to dual antiplatelet therapy, in the current era of timely primary percutaneous coronary intervention. Electronic databases, including EMBASE, MEDLINE, and Cochrane Library, were systematically searched from January 2012 through June 2022. A total of 7,378 publications were screened, and 5 publications were eventually included in this review: 1 randomized control trial and 4 retrospective studies involving 1,461 patients. Data were pooled using a fixed-effects model and reported as odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome of interest was the rate of LVT formation, and the secondary outcomes were the rate of major bleeding and systemic embolism. Pooled analysis showed a significantly lower rate of LVT formation (OR 0.28, 95% CI 0.11 to 0.73, p <0.01) and significantly higher rates of bleeding (OR 2.85, 95% CI 1.13 to 7.24, p = 0.03) in the triple therapy group compared with dual antiplatelet therapy. No significant difference was observed in the rate of systemic embolism between the groups (OR 0.37, 95% CI 0.12 to 1.13, p = 0.08). In this meta-analysis, there is no conclusive evidence to either support or oppose the use of triple therapy for LVT prevention in patients with anterior ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Appropriately powered randomized controlled trials are warranted to further evaluate the benefits of LVT prevention against the risks of major bleeding in this population.