Tumor angiogenesis is essential for tumor growth and metastasis and is dependent on key angiogenic factors. Angiogenin (ANG), a 14.2-kDa polypeptide member of the RNase A superfamily, is an angiogenic protein that has been reported to be upregulated and associated with poor prognosis in some human cancers. The mechanisms through which aberrant ANG levels promote specific steps in tumor progression are unknown. Here, we show that ANG expression in human tissues is strongly correlated with an invasive cancer phenotype. We also show that ANG induces cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth. Novel mechanistic investigations revealed that ANG expression stimulated matrix metallopeptidase-2 (MMP2) expression through the phosphorylation of ERK1/2. Targeting ANG in vivo with N65828, a small-molecule inhibitor of the ribonucleolytic activity of human ANG, resulted in the diminution of xenograft tumoral growth through the inhibition of angiogenesis. Our findings support an unrecognized interplay between ANG, ERK1/2 and MMP2 that can impact tumor growth and progression. The targeting of ANG and associated factors could provide a novel strategy to inhibit tumor establishment and growth.