Currently, there has been an obvious direction for making use of green nanotechnology in the aquaculture sector for maintaining fish performance and health. Therefore, the current perspective is a novel attempt to assess the potential use of green-synthesized titanium dioxide nano-gel (GSTG) fabricated by Caralluma fimbriata as a waterborne on African catfish (Clarias gariepinus) physiological performance, histopathological changes, and Candida albicans infection resis tance. Fish (77.90 ± 4.02 g) were assigned to four treatments, including control (CON), GSTG, C. albicans, and GSTG + C. albicans. The fish of the CON and GSTG groups were intraperitoneally (IP) inoculated with sterile phosphate buffer saline and exposed to 0.00 and 2.00 mg/L of GSTG, respectively. Meanwhile, the fish of the C. albicans and GSTG + C. albicans groups were IP injected with C. albicans (0.30 × 108 CFU/fish) and treated with 0.00 and 2.00 mg/L of GSTG, respectively, for 10 days. Findings revealed that C. albicans resulted in a reduction in fish survival (62.50%) and an occurrence of oxidative stress response. This is indicated by lower activity of glutathione peroxidase and catalase, and higher levels of lipid peroxide (malonaldehyde) and a product of oxidative DNA damage (8-hydroxy-2-deoxyguanosine). Additionally, an elevation in the stress indices (cortisol and glucose) and renal-hepatic functioning biomarkers (creatinine, aspartate aminotransferase, and alanine aminotransferase) was detected in C. albicans-challenged fish. Moreover, altera tions in the histological picture in renal and hepatic tissues were observed, where C. albicans induced necrosis, congestion, degeneration, and inflammatory cell infiltration. Surprisingly, the GSTG application enhanced fish survival to 85.00%, and improved the adverse physiological consequences induced by C. albicans in all measured parameters, besides reviving the injured tissues. Based on the study findings, GSTG exerts a potentially beneficial role in defending C. gariepinus from physiological and health disorders prompted by the C. albicans challenge, and hence, it could be considered a potential remedial measure in the aquaculture sector.