Axl is expressed in various types of cancer and is involved in multiple processes of tumorigenesis, including promoting tumor cell growth, migration, invasion, metastasis as well as angiogenesis. To evaluate further the mechanisms involved in the expression/activation of Axl in various aspects of tumorigenesis, especially its roles in modulating tumor stromal functions, we have developed a phage-derived mAb (YW327.6S2) that recognizes both human and murine Axl. YW327.6S2 binds to both human and murine Axl with high affinity. It blocks the ligand Gas6 binding to the receptor, downregulates receptor expression, inhibits receptor activation and downstream signaling. In A549 non-small-cell lung cancer (NSCLC) and MDA-MB-231 breast cancer models, YW327.6S2 attenuates xenograft tumor growth and potentiates the effect of anti-VEGF treatment. In NSCLC models, YW327.6S2 also enhances the effect of erlotinib and chemotherapy in reducing tumor growth. Furthermore, YW327.6S2 reduces the metastasis of MDA-MB-231 breast cancer cells to distant organs. YW327.6S2 induces tumor cell apoptosis in NSCLC, reduces tumor-associated vascular density and inhibits the secretion of inflammatory cytokines and chemokines from tumor-associated macrophages in the breast cancer model. In conclusion, anti-Axl mAb can enhance the therapeutic efficacy of anti-VEGF, EGFR small-molecule inhibitors as well as chemotherapy. Axl mAb affects not only tumor cells but also tumor stroma through its modulation of tumor-associated vasculature and immune cell functions.