Hepatocellular carcinoma (HCC) comprises the majority of primary liver cancers and possesses a low 5-year survival rate when in the advanced stages. Anillin (ANLN), a key player in cell growth and cytokinesis, is implicated in HCC development. Currently, no treatment agents are known to suppress ANLN. Analysis of The Cancer Genome Atlas data showed that high ANLN expression is associated with poor prognosis and survival in HCC patients. ANLN knockdown was shown to inhibit proliferation, cell cycle progression, and PD-L1 expression in liver cancer cells. The antipsychotic drug penfluridol was identified to suppress ANLN expression in the Connectivity Map analysis. Penfluridol downregulated ANLN at both the mRNA and protein levels, leading to G2/M cell cycle arrest and reduced colony formation in liver cancer cells. Mechanistically, penfluridol inhibited the transcription factor MYC from binding to an E-box motif in the ANLN promoter. This process was mediated by penfluridol-induced upregulation of NRF2, which competitively bound and sequestered MYC away from the ANLN promoter. Penfluridol inhibited the interaction between NRF2 and KEAP1, increasing NRF2. In a syngeneic mouse model, penfluridol suppressed liver tumour growth accompanied by increased NRF2 and decreased MYC and ANLN expression. These findings suggest penfluridol can be applied as the first ANLN blocker to modulate the MYC/NRF2/KEAP1 axis.