This 60-day study aimed to examine the efficacy of a diet supplemented with mandarin peel powder (MP) in enhancing the health and survival of Oreochromis niloticus under suboptimal temperature conditions (21 ℃). One hundred and eighty Nile tilapia fish (22.51 ± 0.04 g) were randomly distributed into four experimental groups; each of 3 replicates (15 fish per replicate). The first group (CONT) received a basal diet without MP. The second (MP10%), third (MP15%), and fourth (MP20%) groups were fed diets containing 10, 15, and 20% MP powder, respectively. At the end of the feeding trail, growth performance, serum growth hormone, α-amylase enzyme, lysozyme activity, nitric oxide, protease activity, globulin, serum levels of IL-1ß, antioxidant status, and intestinal histology were measured. The results showed insignificant differences between CONT, MP15%, and MP20% groups in the final body weight and specific growth rate. The growth hormones in the MP15% and MP20% groups did not show a significant difference compared to fish fed a normal basal diet (CONT). However, the amylase enzymes were significantly greater in both groups. The MP20% and MP15% groups showed a significant increase in antioxidant, lysozyme, nitric oxide, and protease activities compared to CONT. The results also showed that fish that were fed a diet with MP had significantly less of the pro-inflammatory cytokine interleukin-1 beta, and their intestinal villi got wider, especially in the MP20% group. It could be concluded that feeding tilapia on a diet with 20% MP is an effective strategy to improve their health when the temperature is below 21 °C. This is because the fish exhibit higher levels of antioxidant activity, reduced pro-inflammatory responses, and improved intestinal health without difference in the growth performance in compared to control group.