Aberrant angiogenesis of hepatocellular carcinoma (HCC) leads to tumor growth and local or distant metastasis. Uncovering the underlying mechanisms for the neoangiogenesis of HCC can provide novel potential therapeutic targets in the clinic. Here, we reported that serine/threonine homeodomain-interacting protein kinase 2 (HIPK2) was frequently downregulated in HCC tissues compared with the adjacent normal tissues, and patients with lower HIPK2 protein expression were associated with worse overall survival. Both in vitro and in vivo, HIPK2 inhibited the migration of HCC cells, as well as tumor growth and metastasis in xenograft and orthotopic syngeneic HCC mouse models. Furthermore, HIPK2 inhibited the angiogenesis in HCC tumors. Under the hypoxic condition, HIPK2 knockdown enhanced the angiogenesis and the key regulator, HIF-1α signaling pathway; however, HIPK2 overexpression downregulated the tumoral angiogenesis and HIF-1α signaling. In HCC cells, HIPK2 could directly bind to HIF-1α and stimulate the ubiquitination of HIF-1α for proteasomal degradation. HIF-1α knockout partially rescued the promoting effect of HIPK2 depletion on angiogenesis and tumor growth. In conclusion, the downregulation of HIPK2 could enhance the angiogenesis in HCC through inducing the HIF-1α pathway, and further contribute to tumor growth and metastasis, which may provide a novel therapeutic strategy for HCC.