Hepatic artery ligation (HAL), transarterial embolization (TAE), and transarterial chemoembolization (TACE) have been treatment choices for unresectable hepatocellular carcinoma (HCC). Obstruction of tumor blood supply is one of the most important mechanisms of these therapeutics measures. Here we introduced HAL into a metastatic human HCC orthotopic nude mouse model (using MHCC97L and HepG2 cell lines) to examine the effects of hepatic blood flow obstruction on the metastatic potential of hepatic tumor cells, and to investigate the mechanisms underlying these effects. Our results indicated that HAL inhibited tumor growth but concomitantly elicited tumor adaptation and progression, with increased potential for invasion and distant metastases. The underlying proinvasive mechanism of HAL appeared to be associated with enhanced intratumoral hypoxia and epithelial-mesenchymal transition (EMT) due to hypoxia. This was in accord with the in vitro response of MHCC97L and HepG2 cells to hypoxia. The therapeutic effects of HAL could be enhanced by the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002, through arrest of EMT in hepatic tumor cells. It could be useful in the development of mechanism-based combination therapies to enhance the initial antitumor response.