Cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) are the keys to the pathogenic role of Helicobacter pylori and the high-risk factors for the progression of gastric precancerous lesions. Autophagy can stabilize the intracellular environment, resist Helicobacter pylori infection, prevent the accumulation of damaged DNA, and inhibit the proliferation of gastric precancerous variant cells. However, CagA and VacA can inhibit the activation of upstream signals of autophagy and the maturation of autophagy-lysosomes in various ways, thus inhibiting the autophagy of gastric mucosal cells in precancerous lesions of gastric cancer. This change can cause Helicobacter pylori to be unable to be effectively cleared by autophagy, so CagA and VacA can persist and promote the inflammation, oxidative stress, apoptosis of gastric mucosal tissue cells, and the glycolytic activity and proliferation of variant cells in gastric precancerous lesions and a series of malignant biological processes. In recent years, the research on drugs specifically inhibiting the activities of CagA and VacA has become a new direction for the prevention and treatment of Helicobacter pylori-related severe gastric diseases, and a variety of drugs or components that can precisely and effectively regulate the factors for the treatment of gastric precancerous lesions are emerged, which opens a new strategy for the treatment of gastric precancerous lesions in the future.