This study revealed that PLAGL2 mediated the apoptosis resistance of HCC by activating the C‐MET/STAT3 signaling axis and that SeS2, a potential PLAGL2 inhibitor, exerted prominent anti‐proliferative and apoptosis‐inductive effects in HCC both in vitro and in vivo. Here, STAT3 is linked to hepatocellular carcinoma.