The effect of biofloc (BFT) and clear water (CW) at low (ls) and high-water salinity (hs) in wild juveniles of Penaeus setiferus were evaluated. Four treatments were implemented: hsBFT, lsBFT, hsCW, and lsCW. After 45 days, final weight (FW), weight gain (WG), hepatosomatic index (HSI), and survival rate (SR) were evaluated. Antioxidant activity in muscle and hepatopancreas were measured: superoxide dismutase (SOD), catalase (CAT), glutathione-S transferase (GST), lipid peroxidation (LPO), protein oxidation (PO). The FW and SR was low for lsCW (P < 0.05), whereas the WG and HSI was high in hsBFT and lsBFT (P < 0.05). The integrative biomarker response index (IBR) showed differences between muscle (M) and hepatopancreas (HP). Results showed an increase of SOD and CAT measured from HP for lsBFT treatment. For M, CAT and GST were high only in BFT (regardless of the water salinity). LPO determined from M and HP recorded the high values at hs and ls, respectively. The PO determined in HP showed substantial damage in BFT (regardless of the salinity), whereas the same determination from M was only important for lsCW treatment. When the analyses of variance (ANOVA) were performed, SOD, LPO, and PO were significant in response to salinity (P < 0.05). In contrast, for CAT, the higher activity was due to the rearing system and salinity interaction (P < 0.05). Results suggest that BFT could diminish the stress by stimulating the antioxidant system to maintain the redox balance through a higher enzyme activity and decrease damage in the proteins and lipids of the cells.