Modifying and transforming natural antibacterial products is a novel idea for developing new efficacious compounds. Phillygenin has an inhibitory effect onH. pylori. The aim of the present study was to prepare a phillygenin derivative (PHI-Der) through demethylation and hydroxylation. The minimum inhibitory concentration of 18 strains ofH. pylorifrom different sources was 8–32 μg/mLin vitro, and the activity increased 2–8 times than that of phillygenin. PHI-Der could significantly inhibit the colonization ofH. pylori in vivo, reduce the inflammatory response, and promote the repair of inflammatory damage. Further, we used SwissTargetPrediction to predict that its main targets areALOX5,MCL1, andSLC6A4, and find that it can inhibit bacterial biofilm formation and reduce bacterial infection of cells. It can enhance the intracellular oxidative capacity ofH. pylorito inhibitH. pylorigrowth. Further, it could prevent the oxidation ofH. pylori-infected cells and reduce the inflammatory response, which plays a role in protection. In conclusion, compared to phillygenin, PHI-Der had better antibacterial activity and was more effective in treatingH. pyloriinfection. It has characteristics of high safety, specificity, resistance to drug resistance and better antibacterial activity than phillygenin, it’s a good antioxidant for host cells.