Background: Cardiovascular complications are a leading cause of death in patients with type 2 diabetes (T2D). The GLP-1 receptor agonist (GLP-1RA) semaglutide has shown cardiometabolic benefits in individual studies, but a comprehensive analysis of its effects in both oral and subcutaneous formulations is lacking. Objective: This study aimed to systematically evaluate the impact of semaglutide, in oral and subcutaneous formulations, on major adverse cardiovascular events (MACE) in patients with T2D. Methods: This review adhered to the PRISMA guidelines and included a comprehensive search of PubMed, MEDLINE, and Google Scholar from November 2016 to June 2025. High-quality randomized controlled trials (RCTs) comparing semaglutide with placebo in patients with T2D were included. The primary endpoint was MACE, defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Of the 127 articles screened, 3 trials involving 16,130 participants met the inclusion criteria. The pooled HR for MACE across the SOUL, SUSTAIN-6, and PIONEER-6 trials was 0.83 (95% CI: 0.76–0.92; I² = 25%), indicating a 17% relative risk reduction with low heterogeneity. Adverse event profiles were comparable between the semaglutide and placebo groups. Conclusions: Semaglutide use was associated with a significant and consistent reduction in MACE in patients with T2D, supporting its role as a valuable therapeutic option for combined glycemic control and cardiovascular risk reduction.