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This study delves into the potential of replacing soybean meal (SBM) with corn gluten meal (CGM) in the diet of Litopaeneaus vannamei. We aimed to investigate the effects of a dietary soybean meal replacement on various aspects of shrimp, including survival, biochemical indices, digestive enzymes, metabolomics, and disease resistance against Vibrio harveyi. To conduct the study, we fed 840 juvenile Pacific shrimp seven different diets, each containing varying levels of CGM. The control group received a diet with 0% CGM; the other diets contained 3%, 5%, 7%, 9%, 12%, and 14% CGM. Each group comprised three replicates, and the shrimp were fed their diets for eight weeks. Our findings revealed that the survival rate of the shrimp ranged from 90.83% to 97.50% and did not differ significantly between the control and those fed diet treatments 2–5. Additionally, there were no significant differences in crude protein, moisture, and lipid content. However, we observed that total antioxidant capacity content increased with the dietary inclusion of CGM. Furthermore, malondialdehyde content decreased with increasing CGM levels, while superoxide dismutase increased, indicating no obvious oxidative damage was observed in CGM treatment groups. Interestingly, shrimp fed diets 2 and 3 had considerably lower alanine aminotransferase activity than shrimp in the control group. The disease resistance in shrimp was improved across all treatment groups, with a notably higher CGM inclusion having the highest level of mortality during the challenge test. Finally, we analyzed the metabolomics data and found PCA score plots clearly separated the control group and shrimp fed CGM diets. Our study revealed that a 3% substitution rate of SBM with CGM can enhance survival and immunity, regulate metabolites and improve disease resistance.