This study investigated the potential for chitosan nanogel (CNG) to mitigate adverse consequences of infection by Shewanella spp. in the Nile tilapia, Oreochromis niloticus. A total of 160 fish (average weight = 27.55 ± 1.50 g) were allocated to four treatments, each with four replicates, for 14 days. Fish in the control and CNG only groups were intraperitoneally injected with 0.2 mL of sterile saline and placed in water treated with 0 or 75 μg/L, respectively, of CNG. Fish in the Shewanella and CNG + Shewanella groups were injected with 0.2 mL of Shewanella spp. (0.14 × 105 colony forming units) and placed in water treated with 0 or 75 μg/L, respectively, of CNG. Infection by Shewanella induced hemorrhages on the skin and base of the fins, fin rot, and scale loss. Shewanella infection decreased the activity of glutathione peroxidase and catalase, with increased malondialdehyde concentration. Shewanella decreased the brain neurotransmitters (dopamine and serotonin), total protein, and globulin levels, while it increased serum glucose and cortisol. The hepatic and renal dysfunction indicators alanine aminotransferase, aspartate aminotransferase, and creatinine were significantly increased by Shewanella infection. Histopathological changes were produced in the liver, kidney, gills, and brain of Shewanella-infected fish. Notably, Shewanella-infected fish in CNG-treated water had reduced abnormal signs, stress markers, and hepatic and renal dysfunction indicators. CNG water application elevated the brain levels of neurotransmitters and protein and improved the tissue histology. Overall, CNG as a water application is useful for mitigating the adverse effects of Shewanella spp. in Nile tilapia.