Heat stress (HS) is an environmental challenge affecting animals’ health, productivity and welfare. This work aimed to inspect the protective effect of zinc oxide nanoparticles (ZnNPs) and/or prodigiosin (PRG) against inflammation, immune dysfunction, oxidative stress and endoplasmic reticulum (ER) stress triggered by HS in growing rabbits. Growing weaned rabbits (one hundred males, 35 days of age) were randomly assigned into four groups. The first group was fed a basal diet without supplementation and the 2nd, 3rd, and 4th groups were fed diets containing zinc oxide nanoparticles (ZnNPs, 50 mg/kg diet), prodigiosin (PRG, 100 mg/kg diet) or their mixture (ZnPRG) under HS conditions for eight successive weeks. The dietary inclusion with ZnNPs and/or PRG significantly boosted FBW (final body weight), CBWG (cumulative body weight gain), and FCR (feed conversion ratio) and had no substantial impacts on the CFI (cumulative feed intake) as compared with those in HS one. All supplemented treatments significantly unveiled an increase in the values of RBCs, hemoglobin, and platelets and significant decreases in WBCs, basophils and monocytes with non-statistical effects on hematocrit, MCV, MCHC, neutrophils and eosinophils. Compared with the HS group, all supplemental groups showed a significant reduction in TNFα, IL4, IFN-γ, TLR-4 and amyloid A levels and DNA damage markers (OHdG) and significant increases in the levels of NO and lysosome activity. Rabbits in the ZnPRG group had significantly higher IgG and IgM levels compared to other groups. The highest value of CAT and GSH levels were found in rabbits that received the mixture of ZnNPs (50 mg) and prg (100 mg) in their diets under elevated temperatures. Additionally, both treatments, PRG and ZnNPS, significantly (P<0.001) reduced the values of MDA and MYO, while all treated groups had significantly reduced PC contents compared with the HS group. Co-supplement with ZnPRG showed a considerable restoration in the higher immune expression of reticulum oxidative stress such as GRP78 and IRE1 in hepatic tissues induced by hs conditions. The mixture of ZnNPS and prg presented more robust effects in mitigating the adverse impacts of hs in rabbits compared with the individual treatments. Collectively, ZnNps and/or PRG alleviated oxidative stress and dna damage. In addition, it enhanced the antioxidant capacity and immune function, and downregulated ER stress such as GRP78 and IRE1 signaling in the hepatic tissues of stressed rabbits.