A 12‐week nutritional research was conducted to evaluate the influences of benfotiamine on the growth performance, oxidative stress, inflammation and apoptosis in Megalobrama amblycephala (45.25 ± 0.34 g) fed high‐carbohydrate (HC) diets. Six diets were prepared, containing the control diet (30% carbohydrate, C), the HC diet (43% carbohydrate) and the HC diet supplemented with four benfotiamine levels (0.7125 (HCB1), 1.425 (HCB2), 2.85 (HCB3) and 5.7 (HCB4) mg/kg). HC diet remarkably decreased DGC, GRMBW, liver T‐AOC, SOD and CAT activities, SIRT1 protein expression as well as the mRNA levels of SIRT1, Nrf2, CAT, Mn‐SOD and IL10 in liver compared with the C group, but the opposite trend was found in plasma activities of AST and ALT, and contents of IL1β and IL6, liver contents of MDA and mRNA levels of Keap1, NF‐κB, TNF α, IL1β, IL6, Bax, caspase 3, caspase 9 and P53. As for benfotiamine supplementation, HCB2 diet remarkably increased DGC, GRMBW, liver T‐AOC, SOD and CAT activities, SIRT1 protein expression as well as liver mRNA levels of SIRT1, Nrf2, CAT, Mn‐SOD, IL10 and Bcl2, while the opposite was true for plasma AST and ALT activities, and IL1β and IL6 contents, liver MDA contents as well as mRNA levels of Keap1, NF‐κB, TNF α, IL1β, IL6, Bax, caspase 3, caspase 9 and P53. In summary, benfotiamine (1.425 mg/kg) promoted the growth, and alleviated the oxidative stress, inflammation and apoptosis of M. amblycephala fed HC diets through the SIRT1‐mediated signaling pathway.