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Simple Summary: MDM2 is a ubiquitin E3 ligase, frequently overexpressed in human cancers. A biflavonoid Hinokiflavone was identified by virtual screening to bind the MDM2-MDMX RING domain and inhibit MDM2 E3 ligase activity. Hinokiflavone was shown to downregulate MDM2 and its homolog protein MDMX and inhibit the tumorigenic activity of MDM2 in cancer cells. Hinokiflavone could work as a potential anti-cancer therapeutic agent in malignancies with MDM2 overexpression. The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain. [ABSTRACT FROM AUTHOR]