Hepatocellular carcinoma (HCC) ranks among the most prevalent malignant tumors worldwide, characterized by high mortality rates. TRIM23, an E3 ubiquitin ligase, represents a potential molecular target for anticancer drug development. Additionally, Hexahydrocurcumin (HHC) exhibits notable anticancer activity as a natural product. Here, we aimed to investigate HHC's anti-tumor role in HCC. Molecular docking assays and Cellular thermal shift assays were employed to predict HHC's potential targeting of TRIM23. Immunofluorescence and western blot analyses were conducted to assess HHC's inhibition of TRIM23 expression. Wound-healing, clone formation, and transwell assays were used to evaluate its anti-tumor efficacy. Quantitative proteome analysis and co-immunoprecipitation (Co-IP) were employed to explore and verify HHC's potential mechanism in HCC cells. Subcutaneous HCC tumor-bearing mice were used to further validate HHC's function in vivo. Public databases confirmed TRIM23 as a potential biomarker of HCC, associated with poor prognosis. Molecular docking and Cellular thermal shift assays confirmed HHC as a direct inhibitor of TRIM23. Subsequent in vitro assays demonstrated HHC's ability to impede HCC cell function. Quantitative proteome analysis revealed upregulation of MBNL1, a tumor suppressor, in HHC-treated HCC cells. Rescue analysis further demonstrated MBNL1 as a substrate of TRIM23, directly influencing the phenotypic outcomes of HHC-treated cells. Additionally, subcutaneous HCC tumor-bearing mice confirmed HHC's efficacy in vivo. Our findings underscore TRIM23 as a promising therapeutic target for HCC treatment, with HHC emerging as an effective therapeutic agent by targeting the TRIM23/MBNL1 axis.