Prioritizing water management and maintaining its quality for as long as possible, while lowering related stressors, are crucial for sustainable aquaculture. To achieve this equilibrium, enriched aquafeed with natural immunostimulants is essential to success. In this trend, 6 weeks feeding trial was conducted to evaluate the effects of Ceratonia siliqua syrup (CSS) and Zingiber officinale powder (ZOP) in Nile tilapia (Oreochromis niloticus) reared under a zero-water exchange. The immune-antioxidant, growth, physiological responses, and the antioxidant/ inflammatory pathways-associated genes as well as ammonia tolerance were evaluated. Fish (weighing 25.85 ± 1.42 g) were randomly housed into six groups (n = 30 fish/group; ten fish/replicate; three replicates/ group). The control group was fed a basal diet without any additives. The second (CSS1.25) group was fed a diet supplemented with 1.25% CSS. The third (ZOP0.5) and fourth (ZOP1) groups were fed diets supplemented with 0.5 and 1% ZOP. The fifth (CSS1.25 + ZOP0.5) and sixth (CSS1.25 + ZOP1) groups were fed diets supplemented with 1.25% CSS and 0.5 or 1% ZOP. All treatments were kept without water exchange for 6 weeks. Findings revealed the most notable improvement (P < 0.05) in growth rate (final body weight and specific growth rate) and survival rate in fish fed with dietary ZOP and CSS1.25 + ZOP0.5 diets. Hepato-renal markers (alanine and aspartate aminotransferases, urea, glucose, and cortisol) and lipid peroxides (malonaldehyde)