Angiogenesis plays an essential role in cancer progression, which therefore has become an attractive target for anticancer treatment. Tumor angiogenesis is tightly regulated by multiple signaling pathways that usually function redundantly; in addition, crosstalk between these pathways forms a complicated network that is regulated by compensatory mechanisms. Given the complexity of pathogenic mechanisms underlying tumor angiogenesis, most currently used angiogenesis inhibitors that only target single pathways may be insufficient and probably generate drug resistance, thus, increasing the necessity for development of novel anticancer agents. Traditional Chinese medicines (TCM) are receiving great interest since they have relatively fewer side-effects and have been used for thousands of years to clinically treat various types of diseases including cancer. Pien Tze Huang (PZH), a well-known traditional Chinese formulation that was first prescribed 450 years ago, has long been used as an alternative remedy for cancers. However, the precise mechanism of PZH's anticancer activity remains to be further elucidated. Using a colorectal cancer mouse xenograft model, in the present study, we evaluated the effect of PZH on tumor angiogenesis and investigated the underlying molecular mechanisms. We found that PZH inhibited tumor growth since PZH treatment resulted in decrease in both tumor volume and tumor weight in CRC mice. In addition, PZH suppressed the activation of several signaling pathways such as STAT3, Akt and MAPKs. Consequently, the inhibitory effect of PZH on these pathways resulted in the inhibition of tumor angiogenesis as demonstrated by the decrease of microvessel density in tumor tissues. Moreover, PZH treatment reduced the expression of angiogenic factors including iNOS, eNOS, VEGF-A, bFGF as well as their specific receptors VEGFR2 and bFGFR. Altogether, our findings suggest that inhibition of tumor angiogenesis via suppression of multiple signaling pathways might be one of the mechanisms whereby PZH affects cancers.