AbstractLiver cancer is one of the most common solid tumours, and ranks as the third leading cause of cancer‐associated mortality around the world. This study has linked RNF12 to the pathogenesis of liver cancer. Based on the analysis of patient samples and database data, high RNF12 expression was found in liver cancer, in correlation with worse clinicopathological features and a poor prognosis. Meantime, RNF12 could promote the progression of liver cancer in vitro and in vivo.Mechanistically, RNF12 could interact with EGFR and decrease the internalization of EGFR to activate EGF/EGFR signalling. In addition, PI3K‐AKT signalling takes part in the regulation of liver cancer cell proliferation and migration of RNF12. And AKT inhibitor MK2206 could reverse RNF12‐mediated cellular proliferation and migration in liver cancer. The possibility of the physical interaction between RNF12 and EGFR might lay a foundation to develop intervention strategies for liver cancer prevention and therapy.