Abstract Background The rising prevalence of antibiotic resistance in Helicobacter pylori (H. pylori) has significantly compromised the efficacy of current eradication therapies. Notably, numerous traditional Chinese medicines (TCMs) exhibit potent anti–H. pylori activity, highlighting their promising clinical utility. In this study, we aimed to screen and identify bioactive anti–H. pylori compounds from a comprehensive TCM compound library. Materials and methods We conducted a liquid culture–based screening of a TCM library consisting of 1444 compounds. The anti–H. pylori activities of shortlisted TCM compounds were confirmed by agar-based culture. We also assessed the cytotoxicity of these compounds and their impacts on the production of reactive oxygen species (ROS) and pro-inflammatory factors in vitro. An animal model of H. pylori infection was used to evaluate the antibacterial efficacies of the selected compounds and examine their effects on ROS and inflammation. Results From the TCM library, we identified 8 compounds with superior anti–H. pylori effects as compared with levofloxacin. We subsequently verified the anti–H. pylori properties of 3 of these TCM compounds (ie, alantolactone, decursin, phillygenin, and (+)-usniacin) on agar plate and in animals. These 3 compounds also inhibited H. pylori-induced ROS production and inflammation. Conclusions In vitro and in vivo experiments confirmed alantolactone, decursin, and phillygenin have significant anti–H. pylori activities and potential as new eradication drugs. However, further research is required to elucidate their specific antibacterial mechanisms.