Simple Summary Supplementation of agriculture by-product as functional feed additives in combination with biofloc technology (a sustainable and environmentally friendly technology) has recently gained much attention in aquaculture. In the present study, sugarcane bagasse powder can possibly be applied as a feed additive to improve growth performance, immune response, and immune and antioxidant-related gene expression. We investigated, herein, the effects of dietary inclusion of sugarcane bagasse powder (SB) on Nile tilapia development, mucosal and serum immunities, and relative immune and antioxidant genes. Fish (15.12 +/- 0.04 g) were provided a basal diet (SB0) or basal diet incorporated with SB at 10 (SB10), 20 (SB20), 40 (SB40), or 80 (SB80) g kg(-1) for 8 weeks. Our results demonstrated that the dietary incorporation of sugarcane bagasse powder (SB) at 20 and 40 g kg(-1) significantly ameliorated FW, WG, and SGR as opposed to fish fed basal, SB10, and SB80 diets. However, no significant changes in FCR and survivability were observed between the SB supplemented diets and the control (basal diet). The mucosal immunity exhibited significantly higher SMLA and SMPA activities (p < 0.005) in fish treated with SB diets after eight weeks. The highest SMLA and SMPA levels were recorded in fish fed SB80 followed by SB20, SB40, and SB10, respectively. For serum immunity, fish fed SB incorporated diets significantly ameliorated SL and RB levels (p < 0.05) compared with the control. However, SP was not affected by the inclusion of SB in any diet throughout the experiment. The expression of IL1, IL8, LBP, GSTa, GPX, and GSR genes in the fish liver was significantly increased in fish fed the SB20 and SB10 diets relative to the basal diet fed fish (p < 0.05); whereas only the IL8, LBP, and GPX genes in the intestines were substantially augmented via the SB20 and SB80 diets (p < 0.05). IL1 and GSR were not influenced by the SB incorporated diets (p > 0.05). In summary, sugarcane bagasse powder (SB) may be applied as a feed additive to improve growth performance, immune response, and immune and antioxidant-related gene expression in Nile tilapia.