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Advanced gastric cancer (GC) is one of the most aggressive gastrointestinal malignancies, ADAM (A Disintegrin and Metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biological mechanism of ADAM9 in the progression, proliferation and invasion of GC. First, we detected ADAM’s expression, processing and protease activity in GC cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9 expressing cells, not in low expressing cells. RAV-18 showed in vivo antitumor activity in a GC xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low expressing GC cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in GC proliferation and invasion, and that while expressed in some GC cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site directed antibody, other GC cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced GC.