Hepatocellular carcinoma (HCC) is one of the common malignant tumors of the digestive system and its five-year survival rate is low. Hypoxia is an important feature of HCC, which can promote cell death resistance. However, the key regulator of HCC cell survival remains elusive in the hypoxic condition. Emerging researches have showed that the Hippo signaling pathway is involved in the initiation and progression of HCC. Here, we provide evidence that key downstream effectors YAP and its paralog TAZ play vital role in apoptosis resistance of HCC cells under hypoxia. Knockdown of YAP or TAZ does not affect the survival of HCC cells in normoxic and hypoxic microenvironment. In addition, the rate of apoptosis by knockdown or inhibition of both YAP and TAZ under hypoxic condition is largely higher than which under normoxia. In conclusion, simultaneous knockdown or inhibition of YAP and TAZ promote apoptosis of HCC cells dramatically. To our knowledge, this is the first research to explore the role of both YAP and TAZ in HCC hypoxic microenvironment in vitro and in vivo. Therefore, it may be useful for establishing novel targeted therapies of HCC, especially subtypes with plenty of hypoxic areas.