The study was performed to evaluate the effects of the reduced lactate production by sodium oxamate (SO) on growth performance, lactate and glucose and lipid metabolism and glucose tolerance of Micropterus salmoides fed high-carbohydrate (CHO) diets. In vitro study, primary hepatocytes were incubated for 48 h in a control medium (5.5 mM glucose), a high glucose medium (25 mM glucose, HG) or a SO-containing high glucose medium (25 mM glucose + 50 mM SO, HG-SO). Results indicated lactate and triglyceride (TG) levels, and lactate dehydrogenase a (LDH-a) expression in the HG-SO group were remarkably lower than those of the HG group. In vivo study, M. salmoides (5.23 ± 0.03 g) were fed four diets containing a control diet (10% CHO, C), and three SO contents (0 (HC), 100 (HC-SO1) and 200 (HC-SO2) mg kg-1, respectively) of high-CHO diets (20% CHO) for 11 weeks. High-CHO diets significantly reduced weight gain rate (WGR), specific growth rate (SGR), p-AMPK/t-AMPK ratio, and expression of insulin receptor substrate 1 (IRS1), insulin-like growth factor I (IGF-I), insulin-like growth factor I receptor (IGF-IR), fructose-1,6-biphosphatase (FBPase), peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α) compared with the C group, while the opposite was true for plasma levels of glucose, TG and lactate, tissue glycogen and lipid contents, and expression of LDH-a, monocarboxylate transporter 1 and 4 (MCT1 and MCT4), insulin, glucokinase (GK), pyruvate dehydrogenase E1 subunit (PDH), sterol-regulatory element binding protein 1 (SREBP1), fatty acid synthase (FAS). The HC-SO2 diets remarkably increased WGR, SGR, p-AMPK/t-AMPK ratio, and expression of IRS1, IGF-I, IGF-IR, GK, PDHα, PDHβ, FAS, acetyl-CoA carboxylase 1 (ACC1), PPARα and CPT1α compared with the HC group. Besides, HC-SO2 diets also enhanced glucose tolerance of fish after a glucose loading. Overall, the reduced lactate production by SO benefits growth performance and glucose homeostasis of high-CHO-fed M. salmoides through the enhancement of glycolysis, lipogenesis and fatty acid β-oxidation coupled with the suppression of glycogenesis and gluconeogenesis.