Background Rifaximin, a rifamycin antibiotic, is widely used to treat infectious diarrhea but not commonly used in H. pylori eradication. With its potential advantages of the agent, some studies were conducted on this topic. The aim of this study is to assess effectiveness and safety of rifaximin-containing regimens and to evaluate whether they are alternative choices for H. pylori eradication. Methods Scientific databases including PubMed, EMbase and Cochrane Library were used to identify clinical trials on rifaximin-containing regimens published from January 2000 to October 2021. Review Manager 5.4 and STATA12 were adopted for the systematic review. Results In this study, totally 1025 patients were included from 3 randomized controlled and 9 single-arm studies. It showed that the differences in effectiveness and safety between rifaximin-containing and first-line regimens were not statistically significant in randomized controlled trials. However, the results of the single-arm trials indicated that the eradication and adverse drug reaction rate varied suggesting data instability ( r =38.1%-85.4%, r ADR 0.00–67.5% by ITT analysis). Among them, the eradication rate of pediatric patients ( r =85.4% by ITT analysis) was higher than that of adult patients ( r =38.1–74.5% by ITT analysis). Meanwhile, in all adult subgroups (triple or quadruple, with or without amoxicillin, different duration and rifaximin dose), the results did not show sufficient effectiveness as all the eradication rates did not meet the minimum ideal or ideal target. Conclusion Taken together, rifaximin-containing regimens should not be recommended for H. pylori eradication as they cannot achieve the eradication rate desired.