Sirtuin (Sirt)6 has been implicated in negative regulation of inflammation and lipid metabolism, although its function in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains to be defined. To explore the role of hepatocyte Sirt6 in NASH development, we generated hepatocyte‐specific Sirt6‐knockout (KO) mice that were fed a high‐fat and high‐fructose (HFHF) diet for 16 wk. HFHF‐fed KO mice had increased hepatic steatosis and inflammation and aggravated glucose intolerance and insulin resistance compared with wild‐type mice. HFHF‐induced liver fibrosis and oxidative stress and related gene expression were significantly elevated in KO mice. In the livers of KO mice, nuclear factor erythroid 2‐related factor 2 (Nrf2) was down‐regulated; conversely, BTB domain and CNC homolog 1 (Bach1), a nuclear repressor of Nrf2, were up‐regulated. We discovered that Sirt6, which interacts with Bach1 under basal condition, induces its detachment from the antioxidant response element (ARE) region of heme oxygenase 1 promoter. Furthermore, we found that Sirt6 promotes Nrf2 binding to ARE in response to oxidative stimuli, which leads to the expression of phase II/antioxidant enzymes. Finally, we showed that HFHF‐induced steatosis, inflammation, and fibrosis were ameliorated by adenoviral Sirt6 overexpression. Sirt6 may be a useful therapeutic target for amelioration of NASH by curbing inflammation and oxidative stress.—Ka, S.‐O, Bang, I. H., Bae, E. J., Park, B.‐H. Hepatocyte‐specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up‐regulation of Bach1, an Nrf2 repressor. FASEB J. 31, 3999–4010 (2017). www.fasebj.org—Ka, Sun‐O, Bang, In Hyuk, Bae, Eun Ju, Park, Byung‐Hyun Hepatocyte‐specific sirtuin 6 deletion predisposes to nonalcoholic steatohepatitis by up‐regulation of Bach1, an Nrf2 repressor. FASEB J. 31, 3999–4010 (2017)