Little information is available about the homeostasis and alterations appeared against infestation by nasal myiasis caused by Rhinoestrus spp. larvae in Egyptian donkeys. Therefore, the present work aimed to investigate the hematological and biochemical profiles associated with histopathological features and immunological response developed against Rhinoestrus spp. larvae infestation in donkeys in the winter season. The results revealed that 40 out of 80 examined donkeys were infested by nasal myiasis. IgG values were higher (P< 0.01) in infested donkeys (IND) than non-infested ones all over the winter months while the highest mean larval burden was observed in December (11.6 larvae/animal). Neutrophils% in (IND) increased (P<0.01) during December and February. However, an elevation in lymphocytes% (P<0.05) was observed in (IND) during December and January while eosinophils% increased (P<0.01) in all winter months. These results paralleled to the nasal fluid cytological profile in which lymphocytes%, neutrophils% and eosinophils% in (IND) increased (P< 0.05) in December, January and February. Glutathione peroxidase, superoxide dismutase and catalase activities in (IND) were declined (P<0.01) in all winter months. Interleukin-2 (IL-2) and tumor necrosis factor- α (TNF-α) elevated (P<0.05) in December and January. The histopathological picture of turbinate bones, olfactory bulb and meninges reflected the blood and nasal fluid cytological picture as there was lymphocytes infiltration, meningitis and satellitosis. The results indicated that Rhinoestrus spp. infestation in donkeys might affect the vital and immunological processes. In addition, Rhinoestrus spp. infestation in donkeys could linked to oxidative stress and shifting the immune response polarization towards Th2 cytokines.