Sustained anti-angiogenesis therapy increases the level of tumor hypoxia, leading to increased expression of HIF-1a, thereby contributing to the resistance to anti-angiogenesis therapy in hepatocellular carcinoma (HCC). Here, we report that phenazine biosynthesis-like domain-containing protein (PBLD) inhibits hypoxia-induced angiogenesis via ERK/HIF-1a/VEGF axis in HCC cells. Bioinformatic analysis of the TCGA database and clinical samples validation also identify a negative correlation between PBLD and angiogenesis-related genes expression including HIF-1a. Apart from the downregulation of HIF-1a/VEGF expression in HCC cells, PBLD also blocks VEGF receptor 2 (VEGFR2) on endothelial cells via HCC-derived exosomal miR-940. PBLD also activates TCF4 transcriptional promotion effects on miR-940 by directly interacting with it. Together, PBLD exerts an inhibitory effect on angiogenesis not only via blocking the VEGFR2 expression in endothelial cells, but also through downregulating HIF-1a-induced VEGF expression and secretion in HCC cells. These explorations may provide a theoretical basis for exploring new targets and strategies to overcome resistance to anti-angiogenesis therapy.