Here, we demonstrated that (1) GDF15 was significantly increased in chemotherapy‐damage to HCC cells; (2) GDF15 from chemotherapy‐damaged HCC cells promoted the in vitro proliferation, migration and tube formation of endothelial cells; (3) the pro‐angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK and NF‐κB signaling, which was blocked by thalidomide; (4) thalidomide significantly attenuated the in vivo chemotherapy‐damaged HCC cells‐promoted angiogenesis. This evidence concerns the gene NFKB1 and hepatocellular carcinoma.