An 84-day experiment was conducted using a biofloc system to investigate the effects of two different protein levels and varying water salinity levels on the growth performance, feed utilization, whole body composition, survival rate, and health status of red tilapia. One hundred and forty-four fish were divided into six treatments with an average initial weight (12± 0.1g). Two levels of crude protein (CP25, CP30) and three levels of salinity (0ppt, 18ppt. and 36ppt) were designed to establish six treatments of S0CP25, S0CP30, S18CP25, S18CP30, S36CP25 and S36CP30. No significant differences were recorded among treatments regarding fish performance. The experimental factors had no effect (P> 0.05) on all water quality parameters, except for TAN and DO values. The results revealed that the feed intake, and protein efficiency ratio increased significantly (P≤ 0.05) at the salinity level of 18ppt. The survival rate showed no significant differences among treatments. Furthermore, the total heterotrophic bacteria (THB) group was higher in fish intestines. Increasing salinity to 36ppt stimulated the growth of total vibrio counts (TVC) and increased TVC/THB ratios in the water. No significant differences were recorded in blood biochemical analysis, except for GOT values. The lowest significant value of GOT was recorded in S36CP30, while the highest value was observed in S0CP30. The histological sections of the liver and intestines did not show any changes and were normal in all treatments. Regarding our study, red tilapia can be cultured under biofloc conditions within different salinity levels, with no significant effect on fish performance feeding on low-protein die (25%).