This study investigated the protective effects of Astragali Radix against radiation-induced brain injury in mice and explored its underlying mechanisms. A total of 60 male Kunming mice were randomly assigned to six experimental groups: control group, model group, idebenone-treated group, and three Astragali Radix treatment groups receiving low (2.145 g/kg), medium (4.29 g/kg), or high (8.58 g/kg) doses. All mice received daily oral gavage administration for seven consecutive days. Subsequently, a radiation-induced brain injury model was established through a single exposure to 20 Gy X-ray irradiation. Following irradiation, the same gavage administration regimen was continued for an additional seven days in all groups. Histopathological changes in the dentate gyrus of the hippocampus were evaluated using Nissl staining. Cognitive function was evaluated using the Morris water maze test. Oxidative stress markers, including superoxide dismutase (SOD) activity, glutathione (GSH) content, and total antioxidant capacity (T-AOC), were quantified in brain tissue. The expression levels of nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream antioxidant targets, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1), were assessed using Western blot and ELISA. Immunofluorescence staining was performed to evaluate the expression and localization of NRF2 in brain tissue. The results showed that compared with the model group, Astragali Radix treatment significantly improved the general health condition of irradiated mice, although no statistically significant differences were observed in body weight gain, food intake, or water consumption across groups. Histological analysis demonstrated that Astragali Radix effectively attenuated radiation-induced neuronal damage and increased the number of Nissl-stained neurons in the hippocampus. Behavioral assessments using the Morris water maze revealed that Astragali Radix significantly reduced escape latency, increased the frequency of platform crossings, and prolonged the time spent in the target quadrant, indicating a marked improvement in spatial learning and memory function. Furthermore, Astragali Radix administration enhanced antioxidant capacity, as evidenced by elevated levels of SOD, GSH, and T-AOC in brain tissues. Western blot and ELISA analyses demonstrated that Astragali Radix upregulated the expression of NRF2 and its downstream antioxidant enzymes, including HO-1, NQO1, TRX1, and TRXR1. Immunofluorescence staining demonstrated that Astragali Radix significantly enhanced NRF2 expression in the cerebral cortex of mice. Taken together, these results suggest that Astragali Radix exerts neuroprotective effects against radiation-induced brain injury, potentially through activation of the KEAP1-NRF2 signaling pathway, thereby enhancing endogenous antioxidant defenses and alleviating oxidative stress.