The abiotic and biotic stress is an episode that effect on regulatory, neuro-endocrine and immune systems of animals including fish. The stress creates stimulatory and suppressive of immune system resulting in increases the incidence of infection. In view of these points, we have conducted an experiment to mitigate the stress through a nutritional approach through Zinc (Zn) supplementation in Pangasius hypophthalmus (initial weight-3.65 ± 0.75 g). Three isocaloric and isonitrogenous diets with graded levels of zinc 0, 10 and 20 mg/kg were prepared and fed to seven different groups with each in triplicate. The experimental group as follows as normal water with control diet (Ctr/Ctr), lead (Pb) exposed and fed with control diet (Ctr/Pb), control diet and exposed to Pb and temperature (Ctr/Pb-T), Zn 10 mg/kg fed without stressors (Zn- 10 mg/kg), Zn 20 mg/kg fed without stressors (Zn-20 mg/kg), Zn 10 mg/kg fed and Pb and temperature exposed (Pb-T/Zn 10 mg/kg) and Zn 20 mg/kg fed and exposed to Pb and temperature (Pb-T/Zn 20 mg/kg). The Pb in treated water was maintained at the level of 1/20th of LC50 (4 ppm) and temperature at 34 °C in exposure groups. The neutraceuticals role of dietary Zn was studied in terms of antioxidative enzymes (catalase, superoxide dismutase, glutathione-S-transferase), stress markers (Heat shock protein 70, cortisol, acetylcholine esterase, blood glucose, Vitamin C), immunological parameters (Total protein, albumin, globulin, A/G ratio and NBT) and subsequent challenge with Aeromonas veronii biovar sobria. The antioxidative enzymes, stress markers, albumin were significantly (p < 0.01) elevated, brain AChE and immuno-hematological parameters were significantly (p < 0.01) decreased due to lead (Pb) and temperature exposure. The relative survival (%) was reduced due to the concurrent effect of Pb, high temperature stress and bacterial challenge. Zinc at the rate of 10 and 20 mg/kg was found to be restore the biochemical and immunological parameters against concurrent exposure to lead (Pb), temperature and pathogenic infection. Results obtained in the present study indicate that supplementation of 10 and 20 mg/kg of Zn in the diet has a definitive role in the mitigation of lead (Pb) and temperature exposure along with pathogenic infection in P. hypophthalmus.