Background: Dual antiplatelet therapy is an essential component in the management of acute coronary syndrome (ACS) but with a significant risk of bleeding. Newer third-generation P2Y12 inhibitors have proven to be more efficacious but have increased the risk of bleeding. This meta-analysis will study the difference in risk of gastrointestinal bleeding in clopidogrel vs. third-generation oral P2Y12 inhibitors. Methods: A literature search was done in two databases (PubMed/Medline and Cochrane Central). All studies meeting the inclusion criteria assessing the occurrence of gastrointestinal bleeding following the use of oral third-generation P2Y12 inhibitors or clopidogrel were systematically identified. A random-effects meta-analysis evaluated the two arms’ risk ratios (RR). Results: A total of 16 studies were included in our analysis, 11 of which compared ticagrelor to clopidogrel and 5 of which compared prasugrel to clopidogrel. The combined risk for both third-generation P2Y12 inhibitors, Ticagrelor and Prasugrel, was as follows [RR: 1.31 (1.15–1.49); P < 0.0001]. Heterogeneity was reported to be I ² = 4%. Conclusion: Oral third-generation P2Y12 inhibitors were associated with an increased occurrence of gastrointestinal bleeding compared to clopidogrel.