<p>This study evaluated the effects of different salinity levels on the nursery phase of <i>Oreochromis niloticus</i> in a biofloc system, focusing on water quality, zootechnical performance, and hematological parameters. The 42-day experiment was conducted using 18 tanks (100 L each) stocked with 40 tilapia fingerlings (1.14 kg m⁻³) of approximately 2.86 g. Fish were exposed to salinities of 1, 5, 10, 15, 20, and 25 ppt, with three replicates per treatment in a randomized design. Water quality remained within acceptable limits throughout the trial due to the biofloc technology, although increased ammonia concentrations were observed at 10 ppt and elevated nitrite levels at 25 ppt. Regarding zootechnical performance, final weight (g) and uniformity (%) were statistically higher in the 1 ppt treatment and lower in the 25 ppt treatment. Survival and growth were negatively affected at 25 ppt, where the highest incidence of body lesions was also recorded. Hematological analyses revealed that fish cultured at higher salinities exhibited decreases in red blood cells (RBC), white blood cells (WBC), and hematocrit values. Notably, RBC and hematocrit levels were higher in healthy fish compared to injured fish within the 20 and 25 ppt treatments. Overall, the results indicate that <i>O. niloticus</i> cultivation in a biofloc system is feasible at salinities up to 15 ppt without compromising performance or hematological health. However, salinities of 20 and 25 ppt, despite survival rates above 80%, are unsuitable due to health impairments such as body lesions and fin rot, which compromise fish performance and welfare.</p>