Helicobacter pylori (H. pylori) dysregulates the expression of various genes resulting in gastric precursor lesions and cancer. Meanwhile, ornithine decarboxylase (ODC) is a key enzyme that catalyzes the formation of polyamines which are critical for cell growth. So far, the possible regulation of ODC by H. pylori and its virulence factors, and the associated mechanism in gastric epithelial cells remains undefined. In the present study, we found that cellular ODC protein was upregulated by wild-type H. pylori infection and ectopic expression of a cytotoxin-associated gene A (CagA). As a negative control, there was no such effect by cagA-mutant H. pylori infection. Results of signal protein inhibitor treatment demonstrated that the Src, MEK (mitogen-activated protein kinase kinase) and ERK (extracellular signal-regulated kinase) pathway was involved. Moreover, when c-Myc was inhibited, the stimulatory effect of CagA on ODC expression was abolished. Clinically, a positive correlation between c-Myc and ODC expression was observed in patient-derived abnormal gastric tissues. These results implied that the Src/MEK/ERK/c-Myc pathway was required for CagA-mediated ODC induction. Finally, inhibition of ODC expression led to decreased foci formation of gastric epithelial cells before and after H. pylori infection, and ODC protein was over-expressed in precancerous gastric lesions and primary gastric cancer. Collectively, our findings provide new insights into the mechanism behind H. pylori-infection-associated gastric diseases.