Background: Proton pump inhibitors (PPIs) are used to prevent gastrointestinal hemorrhage in patients with coronary treatment undergoing dual antiplatelet therapy (DAPT). Methods: A systematic review was performed to compare the outcomes between DAPT and DAPT + PPI in acute coronary syndrome (ACS) patients or patients who took percutaneous coronary intervention (PCI) with coronary stent implantation (PCI patients), and to estimate, for the first time, the sample size needed for reliable results via trial sequential analysis (TSA). The PubMed, EMBASE, the Cochrane Library and Web of Science databases were searched for articles authored from the onset until November 1, 2022, for randomized controlled trials (RCTs) comparing outcomes in ACS or PCI patients who undertook DAPT or DAPT + PPI. The primary outcomes were the incidence rate of gastrointestinal events and major adverse cardiovascular events (MACEs). Results: The initial web search retrieved 786 literature references. Eventually, eight articles published between 2009 and 2020 were incorporated into the systematic review and meta-analysis. The combined results established a non-significant variation in MACEs incidences between the DAPT group and DAPT + PPI group [risk ratio (RR) = 0.93, 95% confidence interval (CI) = 0.81–1.06, p = 0.27, I{}^{\mathrm{2}} = 0%]; conversely, the incidence of gastrointestinal events was significantly decreased in the DAPT + PPI group in comparison with the DAPT group (RR = 0.33, 95% CI = 0.24–0.45, p 0.00001, I{}^{\mathrm{2}} = 0%). TSA of MACEs and gastrointestinal events revealed that meta-analysis included adequate trials (required sample size = 6874) in the pool to achieve 80% study power. Conclusions: Based on our results, DAPT + PPI can significantly reduce gastrointestinal outcomes without affecting cardiovascular outcomes in PCI and ACS patients compared to DAPT.