Simple SummaryProteins are the highest-cost nutrients of aquafeed and are the essential components in diets and, thus, are acknowledged as the most critical input in aquafeed. The utilization of alternative sources to prepare cheaper feed is requisite to ensure the sustainability of the aquaculture sector. Carbohydrates are the least-expensive form of energy source in practical diet ingredients, more available than proteins, and efficiently used by omnivorous warm-water fishes. The use of carbohydrate-based diets has the advantage of being economically efficient, owing that fish would efficiency utilize the low-cost carbohydrate. Factors that affect the carbohydrate utilization efficiency are carbohydrate origin, dietary level, physical state, technological treatments, and molecular complexity. Also, they can adversely affect fish health through metabolic disorder and physio-clinical signs such as hyperglycemia, increment of glycogen deposition, liver hypertrophy, and histopathological development. Physiological and biochemical characteristics are recognized as a useful tool in the evaluation of the metabolic functions, health status and welfare of farmed species. With reference to our study, knowledge of the physiological and health implication of dietary carbohydrate helps fish nutritionists to tailor and improve the nutritional profile of the diet and hence to provide more adequate and healthy diets for fish.A 45-day feeding trial was conducted to assess the capacity of juvenile Nile tilapia (2.12 ± 0.02 g) to utilize different sources of carbohydrate in their diets. Growth performance, nutrient digestibility, hematological parameters, and hepatic oxidative stress were evaluated. Four experimental diets were formulated to be isonitrogenous (25% crude protein) and isolipidic (10% crude lipid), each containing 20% glucose (GLU-diet), maltose (MAL-diet), dextrin (DEX-diet), and corn starch (CST-diet), respectively. At the end of feeding trial, survival in all groups was above 90% and was not significantly different among groups. The results indicated that fish fed the DEX-diet and CSTA-diet showed significantly (p < 0.05) better specific growth rate (SGR), feed conversion ratio (FCR), and protein efficiency ratio (PER) compared with those fed the other diets. The dry matter and carbohydrate digestibility were significantly higher (p < 0.05) in groups fed on dextrin and corn starch diets. However, the digestibility of crude protein and energy in diets did not differ significantly (p > 0.05) among groups fed on experimental diets. The activities of analyzed antioxidant enzymes in the liver were significantly (p < 0.01) higher in groups fed on glucose and maltose diets when compared to other groups. Hematological parameters were affected by the dietary carbohydrate sources; there was a significant increase in hematocrit (Ht), hemoglobin (Hb), and mean corpuscular volume (CMV) in the blood of fish fed on dextrin and cornstarch diets compared to other experimental diets. These results indicated that low complexity carbohydrate sources induced oxidative stress and depressed growth performance. Overall, these results indicate that dietary dextrin and starch were more efficiently utilized than glucose as an energy source by juvenile Nile tilapia. This information is of increasing interest in fish nutrition to provide healthy and economically feed formulations.