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Introduction: Helicobacter pylori is a risk factor for the development of peptic ulcers with autophagy dysfunction. Omeprazole was widely known as the first-line regimen for H. pylori-associated gastritis. Objectives: The objective of this work was to assess the role of omeprazole on cell pyroptosis and autophagy. Methods: The clinical samples were collected. Quantitative polymerase chain reaction, western blotting, enzyme linked immunosorbent assay, and immunofluorescence (IF) analysis were conducted to reveal the mechanism of omeprazole on cell pyroptosis and autophagy. Results: The results revealed that omeprazole could decrease cell pyroptosis, which was attributed to the downregulation of cleaved caspase-1 expression, resulting in the inhibition of gasdermin E and interleukin-18/1β maturation and secretion as well as the resolution of inflammation. Mechanistically, omeprazole treatment led to drastic downregulation of mammalian target of rapamycin (mTOR) activity was observed in BGC823 cells, leading to enhanced autophagy characterized by increased LC3II expression, which further reduced cell pyroptosis. This omeprazole-mediated phenomenon was enhanced after phosphodiesterase-4 (PDE4) inhibitor dipyridamole (DIP) treatment. In addition, activation of mTOR by MHY1485 could rescue the suppression of cell pyroptosis induced by omeprazole. Most importantly, IF analysis suggested that phosphorylation of mTOR and PDE4 activity and caspase-1 were enhanced in H. pylori-infected gastric mucosa. Conclusion: These findings indicate that omeprazole suppresses cell pyroptosis through PDE4-mediated autophagy in gastric epithelial cells, and DIP enhanced the omeprazole-mediated inhibition of cell pyroptosis, implying that DIP is an alternative combined therapy strategy in improving the treatment of patients with H. pylori infection. [ABSTRACT FROM AUTHOR]