Gastric cancer is highly correlated with Helicobacter pylori (H. pylori) infection. Approximately 50 % of the population worldwide is infected with H. pylori. However, current treatment regimens face severe challenges including drug resistance and gut microbiota disruption. An integrative treatment with slight negative influences on intestinal flora, conforming with concepts of integrative prevention of gastric cancer, is urgently needed. Non-antibiotic responsive biomaterials can respond to different stimuli, including pH, enzymes, light, ultrasound and magnetism, under which biomaterials are specifically activated to perform antibacterial capabilities, while neutral intestinal microenvironments differ from gastric microenvironments or inflammatory sites and have no or minimal irradiation via precisely controlled exogenous stimuli, which may not only overcome antibiotic resistance but also avoid gut microbiota disorders. First, the latest progress in responsive biomaterials against H. pylori without gut microbiome disturbance and their anti-H. pylori performances are profoundly summarized. Second, the mechanisms against planktonic bacteria, biofilms and intracellular bacteria are discussed respectively. Finally, the strategies of specific and targeted H. pylori elimination by responsive biomaterials are introduced. Additionally, the challenges and the focus of future research on translation into clinical application are fully proposed. Antibiotic-free responsive biomaterials for specific and targeted H. pylori eradication represent an innovative approach.