Updated project metadata. Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. Scutellarein, derived from the traditional Chinese herb Scutellaria baicalensis, has shown potential against HCC, albeit with limited efficacy. To enhance its therapeutic potential, we synthesized a novel scutellarein derivative, TBS6b, incorporating the antitumor active moieties trimethoxyphenyl and benzimidazole. TBS6b exhibited significantly enhanced anti-HCC activity, surpassing its precursor in both in vitro and in vivo models. Comprehensive assays, including colony formation, EdU incorporation, wound healing, and Transwell migration, demonstrated TBS6b's potent inhibition of HCC proliferation, migration, and invasion. Notably, TBS6b's mechanism of action was elucidated as promoting the ubiquitination and subsequent degradation of the atypical chemokine receptor 3 (ACKR3), a key regulator of HCC's aggressive behavior. Rescue experiments further confirmed that ACKR3 downregulation is central to TBS6b’s anti-cancer efficacy. This study not only identifies ACKR3 as a novel therapeutic target in HCC but also introduces TBS6b as a promising candidate for HCC treatment, offering a new avenue for therapeutic intervention in this lethal disease.