Taken together, our study demonstrated that geniposide could be an inhibitor of angiogenesis in HCCby directly targeting the TLR4/MyD88‐regulated STAT3/Sp1 pathway followed by the suppression of VEGF transcription in a HIF‐1α independent manner, which provides a novel mechanism for VEGF inhibition in HCC management. Here, SP1 is linked to hepatocellular carcinoma.