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Whether the use of acid suppressants can reduce non-vitamin K oral anticoagulants (NOACs)-related gastrointestinal bleeding (GIB) remains unclear. To systemically evaluate the effect of acid suppressants on the risk of GIB in patients treated with NOACs. All related studies were searched in four databases (Cochrane, Embase, PubMed, and Web of Science) from their establishment to August 10, 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to identify studies and Stata 16.0 software was used for meta-analysis, including sensitivity and subgroup analysis. Six retrospective cohort studies were included in this study. The use of acid suppressants significantly reduced the GIB risk in patients taking NOACs, with an overall relative risk (RR) of 0.70 (95% confidence interval [CI]: 0.61-0.82; P