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Freshwater scarcity poses challenges to aquaculture worldwide, including countries like Egypt. In this study, we investigate the feasibility of integrating underground saline water (USW) with varying salinities into a Biofloc (BFT) system for desert mariculture of Florida red tilapia (FRT) and its impacts on water quality, fish performance and health. Four BFT treatments (C/N ratio = 15) were examined in triplicate using four salinity levels 0 ppt, 12 ppt, 24 ppt and 36 ppt, expressed as S0, S12, S24 and S36, respectively. For 75 days, a total of 12 fiberglass tanks (each 250 L−1 water) were used to store FRT fry (average weight of 1.73 ± 0.01 g/fish). The fish were fed an experimental diet (protein/fat = 30/5) and an additional carbon source of rice bran. The results revealed that group S12 showed better growth indicators, higher survival rate, lower FCR, and lower ammonia levels, while group S0 exhibited lower growth indicators (final weight, weight gain, and specific growth rate) than all groups. The serum kidney, liver, and antioxidant indices performed better in the S12 group. At 12 ppt, the immune-related parameter (IgM) increased by 22.5%, while the stress parameter (cortisol) decreased by 40.8% compared to the S0 group. The liver and intestinal histopathological results revealed that the S12 and S24 groups performed better. Pathogenic bacterial load counts favored the S24 group, which had the lowest number among the groups studied. The recommended salinity for FRT cultivation in USW and BFT is 19.94-20 ppt, determined by polynomial regression of FW and FCR. [ABSTRACT FROM AUTHOR]