Sirtuin 6 (Sirt6) is an NAD+‐dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue‐specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver‐specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle‐related proteins and the immuno staining of Ki‐67 and 5‐bromo‐2‐deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m‐TOR and Akt activity, which is an important pro‐proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl₄)‐induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m‐TOR and Akt activity.