Sheep pox infection poses a significant socio-economic threat to sheep production worldwide. Vaccination is the most effective preventive measure against this disease. This study examines the immunomodulatory effects of various immunostimulants on the immune response of Barki ewes to the live-attenuated sheep pox Vaccine. Sixty Barki ewes were vaccinated with the live-attenuated sheep pox vaccine and divided into four groups: Pox (vaccine only), BCG (vaccine + 0.1 ml BCG), E+Se (vaccine + 0.5 ml/10 kg Vitamin E + Selenium) and Lev (vaccine + 1 ml Levamisole 10%/50 kg). Blood samples were collected to assess humoral immunity (NI), innate immunity, and clinicopathological parameters. The E+Se group showed the best NI, minimal innate immunological alterations, normal hemogram, liver, and kidney function tests, and improved total protein, globulin levels, and neutrophil phagocytic index. The Lev group had NI values close to the Pox group, while the BCG group had lower NI than the Pox group. Innate immunological alterations and haemato-biochemical changes were more pronounced in the Lev and BCG groups compared to the Pox group and in the BCG group compared to the Lev group. Conclusion: The E+Se injection before the live-attenuated sheep pox vaccine significantly enhanced the ewes' humoral immune response and reduced vaccination side effects.