Hypoxia is the most significant factor that threatens the health and even survival of freshwater and marine fish. Priority should be given to the investigation of hypoxia adaptation mechanisms and their subsequent modulation. Acute and chronic studies were designed for the current study. Acute hypoxia comprised of normoxia dissolved oxygen (DO) 7.0 ± 0.5 mg/mL (N0), low-oxygen 5.0 ± 0.5 mg/mL(L0), and hypoxia 1.0 ± 0.1 mg/mL (H0) and 300 mg/L Vc for hypoxia regulation (N300, L300, H300). Chronic hypoxia comprised of normoxia (DO 7.0 ± 0.5 mg/mL) with 50 mg/kg Vc in the diet (N50) and low oxygen (5.0 ± 0.5 mg/mL) with 50, 250, 500 mg/kg Vc in the diet (L50, L250, L500) to assess the effect of Vc in hypoxia. The growth, behavior, hematological parameters, metabolism, antioxidants, and related inflammatory factors of channel catfish were investigated, and it was found that channel catfish have a variety of adaptive mechanisms in response to acute and chronic hypoxia. Under acute 5 mg/mL DO, the body color lightened (P < 0.05) and reverted to normal with 300 mg/mL Vc. PLT was significantly elevated after 300 mg/L Vc (P < 0.05), indicating that Vc can effectively restore hemostasis following oxygen-induced tissue damage. Under acute hypoxia, the significantly increased of cortisol, blood glucose, the gene of pyruvate kinase (pk), and phosphofructokinase (pfk), together with the decreased expression of fructose1,6-bisphosphatase (fbp) and the reduction in myoglycogen, suggested that Vc might enhance the glycolytic ability of the channel catfish. And the enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and the gene expression of sod rose significantly, showing that Vc might improve the antioxidant capacity of the channel catfish. The significant up-regulation of tumor necrosis factor-alpha (tnf-α), interleukin-1β (il-1β), and cd68 under acute hypoxia implies that hypoxia may generate inflammation in channel catfish, whereas the addition of Vc and down-regulation of these genes suggests that Vc suppresses inflammation under acute hypoxia. We found that the final weight, WGR, FCR, and FI of channel catfish were significantly reduced under chronic hypoxia, and that feeding 250 mg/kg of Vc in the diet was effective in alleviating the growth retardation caused by hypoxia. The significant increase in cortisol, blood glucose, myoglycogen, and the expression of tnf-α, il-1β, and cd68 (P < 0.05) and the significant decrease in lactate (P < 0.05) under chronic hypoxia indicated that the channel catfish had gradually adapted to the survival threat posed by hypoxia and no longer relied on carbohydrates as their primary source of energy. While the addition of Vc did not appear to increase the energy supply of the fish under hypoxia in terms of glucose metabolism, but the significantly decreased expression of tnf-α, il-1β, and cd68 (P < 0.05) also were found, indicating that chronic hypoxia, similar acute hypoxia, may increase inflammation in the channel catfish. This study indicates that under acute stress, channel catfish withstand stress by raising energy supply through glycolysis, and acute hypoxic stress significantly promotes inflammation in channel catfish, but Vc assists the channel catfish resist stress by raising glycolysis, antioxidant capacity, and decreasing the production of inflammatory markers. Under chronic hypoxia, the channel catfish no longer utilize carbohydrates as their primary energy source, and Vc may still effectively reduce inflammation in the channel catfish under hypoxia.