Antimicrobial resistance poses challenges to humans and animals, especially to the poultry sector in control of fowl typhoid with antibiotics, leading to increased mortality and food insecurity. Therefore, it is essential to develop more effective medications as alternatives to antibiotics. Currently, zinc oxide and copper oxide nanoparticles are of such significant interest due to their antibacterial properties. This study aimed to evaluate antimicrobial activity of zinc oxide and copper oxide nanoparticles against fowl typhoid in broilers. Ninety broiler chicks were raised under suitable management conditions. On day 10 of age, chicks were divided into six groups: control negative, control positive, T1, T2, T3, and T4. On day 19 of age, chicks in all groups except control negative were infected with Salmonella gallinarum (0.2 mL, 108 CFU/mL). After appearance of clinical signs, the treatments (Florfenicol; 50 mg/L drinking water [T1], and zinc oxide + copper oxide nanoparticles; 25 + 10 mg/kg/d [T2], 37.5 + 15 mg/kg/d [T3], and 50 + 20 mg/kg/d [T4]) were administered to chicks. Chicks were sacrificed on 26th and 30th day of age, and samples of blood and tissue were obtained. Hematological analysis with gross and histopathological examination of spleen, thymus and bursa of Fabricius was performed. Results revealed that there was no visible congestion in spleen and thymus of T3 and T4 at 11th day post infection. Antibody level against new castle's disease and lymphoproliferative response showed no significant difference in all groups. However, phagocytic response in nanoparticles treated groups exhibited a notable (p < 0.01) distinction compared to control positive. Notably, T3 demonstrated the highest level of phagocytic activity. Hematological parameters, including lymphocytes, heterophils, eosinophils, and heterophils/lymphocytes ratio in groups T2, T3, and T4, indicated significant (p < 0.01) difference compared to control positive. However, lymphocytes, heterophils, and heterophils/lymphocytes ratio in groups T2, T3, and T4 showed no significant difference when compared to T1. Nanoparticle treated groups showed decreased (p < 0.01) congestion of spleen and thymus as compared to control positive. Overall, zinc oxide and copper oxide nanoparticles have potential to serve as an alternative to florfenicol in treatment of fowl typhoid.