Helicobacter pylori is a human pathogen that causes gastric diseases such as chronic gastritis, peptic ulcer disease (PUD), and gastric cancer. H. pylori infection also enhances the invasion and metastasis of gastric cancer, but the molecular mechanism involved is unknown. In this study, we examined the molecular mechanism by which H. pylori exploits the urokinase-type plasminogen activator (uPA) proteolytic system for pathogenesis and metastasis-related host cell responses. uPA is a host serine protease that converts plasminogen to plasmin and plays important roles in tissue remodelling and cancer metastasis. Using a plasmin inhibitor and a novel uPA small-molecule inhibitor, we demonstrated that both uPA and plasmin activities contributed significantly to H. pylori-induced host cell motogenic responses. This effect was dependent on the H. pylori oncoprotein, CagA. To further elucidate the molecular mechanism involved, we examined the effect of the specific uPA inhibitor on the total secretome of H. pylori-infected epithelial cells using quantitative mass spectrometry. Our findings indicate that H. pylori broadly alters the abundance profile of a multitude of secreted plasmin substrates, including laminin, transforming growth factor β1, FAM3C, complement C3, and fibrinogen, in a manner dependent on uPA catalytic activity and CagA. Taken together, our findings suggest that H. pylori, through its oncoprotein, CagA, exploits the uPA-plasmin proteolytic cascade for dysregulation of the host extracellular proteome and processes involved in tissue remodelling and cancer metastasis. Whilst uncovering the therapeutic potential of the small-molecule specific uPA inhibitor for hindering H. pylori pathogenesis, this study has identified novel potential drug targets for the intervention of H. pylori-associated gastric disorders and gastric cancer metastasis.