The research aimed to investigate the impact of Yucca schidigera extract on Salmonella enteritidis -infected poultry compared to the fosfomycin drug. 140 salmonella free chickens were classified into first control-negative group and four Salmonella infected groups at nine days old (1×108 CFU/ml orally) orally. The second group acts as a positive group, while the 3rd, 4th, and 5th groups were treated with fosfomycin, Yucca schidigera extract, and both of them, respectively. Fosfomycin was administered at 5 days post infection at 14d old for five days. Yucca extract was administered from day one until the end of the experimental period (42d). The re-isolation of salmonella from the all treated groups after 35 days was negative. Fifth group showed normal liver function enzymes, urea and creatinine; maintain albumin and globulin at normal levels from 14 to 35 days; and keep the normal values of total antioxidants. The fourth and fifth groups displayed highly significant levels of lysozyme at 21 days old followed by a non-significant decrease at 28 and 35 days old, and decrease in relative fold changes of IL-6 compared with the second group. In the fifth group, the hemagglutination inhibition antibody titer was non-significantly higher at 21 and 28 days old, and there was a significant increase at 35 and 42 days old in comparison with the fourth group. Therefore, Yucca schidigera is a safe, effective, biocompatible, and cost-efficient alternative natural product that could be used for the treatment of salmonellosis by enhancement immune response and activated antioxidative capacity.