The efficacy of different biofloc treatments (BFTs) to compensate for a reduction in dietary protein level under zero-water exchange systems was studied during a 10 weeks experiment, assessing the effect on water quality, growth, immune and antioxidant status of Nile tilapia (Oreochromis niloticus) fingerlings. Six groups were established and fed the same plant-based feed containing 20 or 30% crude protein: two groups in clear water conditions with no added carbon source, two biofloc groups given a wheat milling by-product (WMB) as additional carbon source and two biofloc groups given rice bran (RB). The results showed that biofloc volume was higher when WMB was used as carbon source. The highest growth performance were obtained with the biofloc system and the higher dietary protein level. Fish fed 20% crude protein and stocked in WMB biofloc significantly outperformed the fish fed 30% crude protein and stocked in clear water. Significant improvements in hematocrit, white blood cells, lymphocytes, plasma proteins, and humoral (immunoglobulin, lysozyme, myeloperoxidase and ACH50) and cellular (phagocytosis activity and respiratory burst) immune parameters were observed in all BFT fish. BFT also increased superoxide dismutase and catalase activities. Moreover, the fish fed 20% dietary protein and reared in both biofloc conditions showed equal or superior levels of the immunological criteria to fish fed 30% protein in clear water conditions. In conclusion, using WMB as carbon source could make up for a reduction in dietary protein levels of 10% and improve growth performance, and the immune and antioxidant status of O. niloticus.