Background: The Forkhead transcription family member FOXA2 plays a fundamental role in hepatocellular carcinoma ( HCC) progression, but the precise interaction factor and molecular regulation of FOXA2 are not fully understood. Objective: In this study, we found that FOXA2 could interact with sirtuin 6 ( SIRT6) directly in vivo and in vitro. We explored that the expressions of FOXA2 and SIRT6 were significantly downregulated in human HCC and HCC cell lines. Methods: Functionally, cell counting kit-8 assay and Transwell (R) assay were performed; we demonstrated that the knockdown of FOXA2 and SIRT6 promoted HepG2 cells and Huh7 cells proliferation and invasion in vitro. Results: Mechanically, using luciferase reporter assay and fast chromatin immunoprecipitation assay, we showed that FOXA2 and SIRT6 regulated the expression of ZEB2 from transcription level. ZEB2 suppression was involved in the anti-oncogenesis effect of FOXA2 and SIRT6. The negative correlation between the expressions of ZEB2 and FOXA2 or SIRT6 was observed in the tissues of HCC patients. Conclusion: Our findings indicated that the coordination function of FOXA2 and SIRT6 played a critical role in HCC progression and may serve as potential drug candidates for HCC.