This study evaluated the ability of orange peel fragment (OPF) to act as a functional feedstuff, influencing growth, haematological profile, and antioxidant enzyme activity of Nile tilapia subjected heat/dissolved oxygen‐induced stress (HDOIS). A group of 440 male Nile tilapia (31.7 g ± 0.34) was randomly distributed in 40 250‐L aquaria (11 fish/tank) and fed five practical diets with graded levels of OPF at 0%, 0.2%, 0.4%, 0.6%, and 0.8% for 70 days. The diets were formulated to contain 30% crude protein and 18 MJ/kg crude energy. After the feeding period, growth performance was evaluated and six fish per treatment were sampled for haematological profile and antioxidant enzyme activity, before and after HDOIS. Then, fish were subjected to HDOIS (32°C/2.3 mg/L dissolved oxygen) for three days and the same haematological profile and antioxidant enzyme activity were determined. There was no effect of OPF on the haematological profile, either before or after HDOIS. The polynomial regression model was used to express the relationship between antioxidant enzymes activity and OPF supplementation level. The maximum activity of superoxide dismutase, catalase, and glutathione peroxidase was reached at 0.66%, 0.63%, and 0.68% of OPF respectively. Results of the present study suggest that a dietary supplementation level of 0.63%–0.68% of orange peel fragment was appropriate to maintain Nile tilapia haematological profile and improve its antioxidant capacity under HDOIS.