Carbohydrates are an excellent cost-friendly energy source for fish, and they have been used to improve growth performance and reduce dietary protein levels. However, the aquaculture industry has frequently overused high dietary carbohydrate levels, which has caused metabolic disturbances in fish. This deleterious effect is often diagnosed at the end of the production cycle, affects fish health and causes significant losses to farmers. In this context, β-glucan, which is broadly known as an immunomodulator, may ameliorate the deleterious effects caused by high levels of dietary carbohydrates. Therefore, we investigated the effect of dietary β-glucan on the reduction of metabolic disturbances in Nile tilapia fed a high carbohydrate diet. A total of 352 juvenile Nile tilapias (25.39 ± 0.83 g) were fed isoproteic (280 g kg−1 PD) and isoenergetic diets (3130 kcal kg−1) containing low amounts of carbohydrates (CHO-L 270 g kg−1) or high amounts of carbohydrates (CHO-H 620 g kg−1) with four levels of β-glucan (βG; 0, 1, 3 and 6 g kg−1) for 10 weeks. We evaluated the productive performance, plasma glucose, serum triglycerides, hepatosomatic index, total liver and muscle lipid, hepatic glycogen, hepatic activity of hexokinase, glucokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, malic enzyme, liver histopathology and innate immune responses. Fish fed a high carbohydrate diet had significantly increased productive performance and lipogenesis, presenting higher hepatosomatic indexes, triglycerides, hepatic glycogen, muscular lipid, hepatic activity of glucose-6-dehydrogenase phosphate, and malic enzyme. Additionally, histological analyses indicated expressive cytoplasm vacuolization. The innate immune responses such as leukocyte respiratory activity, complement and lysozyme were also significantly decreased for the high carbohydrate diet, indicating the occurrence of immunosuppression in fish. These results also indicate impaired metabolic functioning. However, β-glucan ameliorated metabolic stress. Specifically, we found a significant decrease in the serum levels of triglycerides, hepatosomatic index, muscular lipid, and hepatic activities of malic and glucose-6-dehydrogenase phosphate enzymes in fish fed high amounts of carbohydrates containing glucan. There was also a significant decrease in hepatic activity of the glycolytic pathway, hexokinase and pyruvate kinase. Moreover, β-glucan modulated the respiratory activity of leukocytes and complement, confirming its immunomodulating effect on fish. In conclusion, β-glucan mitigated the metabolic disturbances caused by the high levels of carbohydrates in the diet of Nile tilapia. This finding indicates that besides having an immunomodulating effect, β-glucan also has metabolic functions/benefits such as reducing glycolysis and lipogenesis.