Hypoxia is a key factor in the pathogenesis of angiogenesis, and cysteine‑rich 61 (CCN1), an angiogenic factor, is involved in the development of pathological angiogenesis. The aim of the present study was to investigate the mechanism of CCN1 RNA interference (RNAi)‑induced inhibition of hypoxia‑induced pathological angiogenesis in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions in vitro. The effects of inhibiting phosphoinositide 3‑kinase (PI3K)/Akt signaling using LY294002 were investigated in hypoxic HUVECs. The proliferation and apoptosis of HUVECs under hypoxia were assessed using CCN1 RNAi. The CCN1‑PI3K/Akt‑vascular endothelial growth factor (VEGF) pathway was analyzed under hypoxic conditions using reverse transcription‑quantitative polymerase chain reaction and western blotting. CCN1 RNAi inhibited the proliferation and induced the apoptosis of the HUVECs under hypoxia, with hypoxia significantly increasing the mRNA and protein expression levels of CCN1, Akt and VEGF. By contrast, CCN1 RNAi reduced the mRNA and protein expression levels of CCN1, Akt and VEGF in the HUVECs (P<0.05). Furthermore, LY294002 reduced the mRNA and protein expression levels of CCN1 in the hypoxic cells (P<0.05). These data indicated that CCN1 inhibits apoptosis and promotes proliferation in HUVECs. Therefore, CCN1 RNAi may offer a novel therapeutic strategy, which may aid in the treatment of pathological angiogenesis via inhibition of the PI3K/Akt‑VEGF pathway.