The protein-protein interaction between menin and mixed lineage leukemia (MLL) plays an important role in the development of human hepatocellular carcinogenesis (HCC) and is associated with poor prognosis of HCC patients. Hence, interrupting the menin-MLL interaction is an attractive strategy in cancer treatment, particularly for liver cancer. In this study, we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.