Immunity has a vital role in defending the body against infectious diseases. Phytochemicals stimulate the immune system to defend against diseases. Butternut Squash is one of the highest sources of phytochemicals that have many benefits for immunity, including antioxidants and Immunomodulatory, antitumor properties. This study was conducted to evaluate the possible immunomodulatory effect of Cucurbita moschata “Butternut Squash” at three tested levels on cyclophosphamide-induced immunosuppression. Fifty male adult albino rats weighing (200 ± 10 g) were used in the experiment. Rats were divided into two main groups. The first main group (n=10 rats) was healthy rats and was fed on a basal diet while the second main one (n=40 rats) was injected with CP (40 mg/kg) four times for immunosuppression. These rats were divided into 4 subgroups: Subgroup (1) was fed on a basal diet and kept as a positive control group. The other three subgroups (3): were group 2 and fed the basal diet supplemented with 10, 20 and 30 % whole dried butternut squash, respectively. The supplementation with dried butternut squash significantly (P<0.05) increased the mean value of Immunoglobulins as well as improved the hematological parameters and liver enzymes while white blood cell was significantly (P<0.05) decreased as compared to the positive control group. It was also observed a significant increase in the levels of Catalase, glutathione peroxidase and Glutathione reductase while malondialdehyde was significantly (P<0.05) decreased as compared to the control positive group. Also, the histopathological examination revealed a remarkable improvement in the spleen and liver tissues with varied percentages of improvement between the treated groups compared to the control positive group. It was concluded that Butternut Squash supplementation stimulates the immune system of rats