BACKGROUND: Candida albicans infection induces economic losses in aquaculture practices. Currently, the success of the nanotechnology field has gained more consideration in the aquaculture sector as it bestows favorable impacts in remedies in comparison to traditional practices. OBJECTIVE: The present study was conducted to assess the role of nano chitosan gel (NCG) exposure via water in managing the deteriorating impacts triggered by C. albicans in Nile tilapia, Oreochromis niloticus. Hepato-renal function, behavioral and stress response, neurological function, hepatic antioxidant/oxidant status, and histopathological architectures were investigated. METHODS: A total of 160 fish (average weight: 50.00 ± 6.30 g) were randomly assigned to four groups, each with four replicates: control, NCG, C. albicans, and NCG + C. albicans. The NCG was applied as bath treatment at a concentration of 75 µg/L for ten days. RESULTS: The outcomes demonstrated that the C. albicans challenged fish exhibited obvious behavioral alterations including loss of equilibrium, surfacing, abnormal swimming and movement, and aggression. Infection with C. albicans caused an elevation in hepato-renal biomarkers (alanine and aspartate aminotransferases, alkaline phosphatase, urea, and creatinine), stress-related indices (glucose, cortisol, nor-epinephrine, and 8-hydroxy-2-deoxyguanosine), and lipid peroxides (malondialdehyde). Moreover, it caused a noticeable decline in the hepatic antioxidant indices (total antioxidant capacity and reduced glutathione content) and acetylcholinesterase activity. The hepatic, renal, and brain architectures were severely damaged by the C. albicans challenge, exhibiting significant fatty changes, necrosis, vacuolation, and congestion. Remarkably, the aqueous application of NCG in the C. albicans-challenged fish ameliorated all the aforementioned biomarkers and facilitated the regeneration of histopathological changes. CONCLUSION: Overall, the application of NCG in the aquatic environment is an effective tool for managing C. albicans infection in Nile tilapia. Moreover, it can be utilized in combating stress conditions in the aquaculture sector.