Ionizing radiation can irreversibly damage the brain cells' function and structure. Spirulina platensis (Sp) is widely employed as a dietary supplement because it has anti-inflammatory, antioxidant, and immunomodulating properties. Therefore, this work aims to investigate the protective properties of Sp towards gamma-irradiation (IRR)-induced brain damage. The whole-body male albino rats were exposed to IRR with a 7 Gy single dose in the absence or presence of Sp (400 mg/kg body weight). The rats were divided into four groups: Group I (control), Group II (Sp), Group III (IRR), and Group IV (Sp + IRR + Sp). The biochemical and histopathological investigations were evaluated two weeks post-irradiation. The results showed that irradiation increased inflammation by increasing tumor necrosis factor-alpha (TNF alpha), IL-1B, and IL-6 while decreasing IL-10. Additionally, irradiation evoked nucleic acid damage. Furthermore, IRR provoked oxidative stress. Similarly, the IRR caused neurotransmitter disturbances by increasing S100 calcium-binding protein (S100B) and gamma- aminobutyric acid (GABA) levels while reducing brain-derived neurotrophic factor (BDNF) and glutamate levels in brain tissue. Therefore, Sp alleviated IRR-induced brain damage by attenuating the above-mentioned parameters and ameliorating histopathological changes. Consequently, it could be concluded that Sp might exert a beneficial effect on irradiation-induced brain damage by attenuating oxidative stress, regulating BDNF, and suppressing S100B.