The current study aims to evaluate the possible neuroprotective impact of gold nanoparticles (AuNPs) and an alpha-lipoic acid (ALA) mixture against brain damage in irradiated rats. AuNPs were synthesized and characterized using different techniques. Then, a preliminary investigation was carried out to determine the neuroprotective dose of AuNPs, where three single doses (500, 1000, and 1500 µg/kg) were orally administrated to male Wistar rats, one hour before being exposed to a single dose of 7Gy gamma radiation. One day following irradiation, the estimation of oxidative stress biomarkers (malondialdehyde, MDA; glutathione peroxidase, GPX), DNA fragmentation, and histopathological alterations were performed in brain cortical and hippocampal tissues in both normal and irradiated rats. The chosen neuroprotective dose of AuNPs (1000 µg/kg) was processed with ALA (100 mg/kg) to prepare the AuNPs-ALA mixture. The acute neuroprotective effect of AuNPs-ALA in irradiated rats was determined against valproic acid as a neuroprotective centrally acting reference drug. All drugs were orally administered one hour before the 7Gy-gamma irradiation. One day following irradiation, animals were sacrificed and exposed to examinations such as those of the preliminary experiment. Administration of AuNPs, ALA, and AuNPs-ALA mixture before irradiation significantly attenuated the radiation-induced oxidative stress through amelioration of MDA content and GPX activity along with alleviating DNA fragmentation and histopathological changes in both cortical and hippocampal tissues. Notably, the AuNPs-ALA mixture showed superior effect compared to that of AuNPs or ALA alone, as it mitigated oxidative stress, DNA damage, and histopathological injury collectively. Administration of AuNPs-ALA resulted in normalized MDA content, increased GPX activity, restored DNA content in the cortex and hippocampus besides only mild histopathological changes. The present data suggest that the AuNPs-ALA mixture may be considered a potential candidate for alleviating radiation-associated brain toxicity.