Heat stress (HS) is a threat that can lead to significant financial losses in the production of the poultry industry. As a result, looking for strategies to prevent or mitigate the detrimental effects of HS is imperative and has become a major research topic in poultry science. The most recent strategy to ameliorate HS in poultry is early perinatal programming using the in Ova technology with nanomaterials. Therefore, the current experiment was conducted to evaluate the effects of in Ovo injection (IOI) of nano-curcumin (CurNPs) and nano-zinc oxide (ZnNPs) on blood parameters of broilers and their ability to alleviate heat stress in hatched chicks. Six hundred fertilized eggs (Ross 308) were allocated randomly into five groups with four replicates per group (n = 120). The first group (G1) was kept as an intact control without injection, while the second one (G2) was IOI with the vehicle (sterile distilled water-DW). The remaining eggs were IOI with CurNPs (G3), ZnNPs (G4), and both NPs (G5). Then the hatchlings from each treatment were reared until day 42 of age. The results of research concluded that the IOI of ZnNPs has better results than CurNPs or ZnNPs/CurNPs-treated groups and helps broilers cope with the detrimental effects of heat stress. ZnNPs significantly increase the hematological picture (Hb and PCV), enhance antioxidant and thyroid gland activities, and boost immunity status (increasing H/L ratio, phagocytic activity, and the immune organs weight). Moreover, ZnNPs augment the duodenal morphometric with fewer histopathological alterations of the duodenum and liver, especially under thermostressed conditions.