Candida albicans is a pathogenic yeast recently associated with diverse diseases in aquaculture. The present study investigated the efficacy of chitosan nanogel (CNG) in ameliorating effects of C. albicans on Nile tilapia (Oreochromis niloticus). Fish were randomly distributed into four groups (control, waterborne CNG at 75 μg/L, intraperitoneally challenged with C. albicans (1.8 × 107 CFU/mL), and waterborne CNG at 75 μg/L + C. albicans at 1.8 × 107 CFU/mL). Results showed that C. albicans infection reduced survival rate (57.5%) and caused marked clinical symptoms in fish among all infected groups. Substantial declines in immunological (complement 3, lysozyme, and immunoglobulin M), protein (total protein and non-albumin protein), and antioxidant (catalase, glutathione peroxidase, and superoxide dismutase) biochemical endpoints were exhibited, The C. albicans infected group also showed marked down-regulation in the expression of immune-related genes, including tolllike receptor 2 (TLR-2), transforming growth factor beta2, tumor necrosis factor alpha, interleukins (IL-1β, IL-6, and IL-10), and antiapoptotic gene (B-cell lymphoma, BCL-2). The expression of the apoptotic gene (Bcl-2 associated X protein, BAX) was up-regulated in fish challenged by C. albicans. The application of waterborne CNG to fish challenged with C. albicans infection improved fish survival (79.5%) and all other measured parameters. The main finding of this work was that CNG is a nanotechnology with potential for preventing degraded health status by C. albicans infection in tilapia, and thus has promise as an intervention in aquaculture settings.