The study examines the impact of integrated biofloc technology (BFT), different salinity levels, and their combined effects over 90 days on various physiological parameters. The investigation includes growth performance and feed utilization, water quality, the chemical composition of biofloc and fish, digestive enzymes, reproductive performance, stress and biochemical indicators, and antioxidant-immune responses in red tilapia (Oreochromis spp.) broodstock. The fish were initially weighed (males: n = 270; 104 ± 0.96 g; females: n = 270; 93.2 ± 0.66 g) and subsequently divided into 12 treatment groups (6 for males and 6 for females) spread across 36 separate tanks (3 tanks per treatment; 45 fish per treatment; 15 fish/tank). The treatments involved three salinity levels (18, 28, and 36 ppt) in both clear water (CW) and BFT systems. The outcomes demonstrated that fish in the 36 ppt salinity with BFT treatment demonstrated significant improvements (P < 0.05) in growth parameters (final body weight, weight gain, and specific growth rate, feed intake, and feed conversion ratio). The condition factor in BFT groups increased in all salinity situations. The survival rates of broodstock were consistently high in all experimental conditions The study found that BFT and salinity significantly impacted (P < 0.05) whole body contents (moisture, protein, lipid, and ash) in both males and females. Water quality parameters showed variations between BFT and CW, with notable impacts (P < 0.05) on dissolved oxygen and pH. The BFT and salinity influenced digestive enzyme activities (protease, amylase, and lipase) and reproductive performance (males) and the 36 ppt salinity with BFT recorded the highest values. The hemato-biochemical and antioxidant-immune responses were also impacted by BFT and salinity exposure. The study highlights the potential benefits of incorporating BFT into red tilapia aquaculture systems, particularly in optimizing growth, health, and reproductive performance under various salinity conditions, which can enhance sustainable intensification, disease control, and environmental stewardship.