In this study, we investigated the potential in vivo neuro-protective/therapeutic effects of N-acetyl cysteine (NAC) as an adjuvant supportive agent along head and neck irradiation protocols aiming to minimize the radiation-induced neurotoxicity to non-tumor bystander brain tissues. Experimental animals were randomly assorted into four experimental groups; normal control, cranial irradiated, irradiated pre-treated with NAC and irradiated rats that received NAC post-irradiation. Redox, inflammatory and apoptotic alterations of brain tissues were assessed post animals' sacrifice. Cranial irradiation induced significant oxidative stress, inflammatory and apoptotic reactions in rat brain. However, administration of NAC for two weeks prior to irradiation effectively attenuated the radiation impact on the brain oxidative stress, inflammation and apoptosis. On the other hand, the neuro-protective effects offered by pre-treatment with NAC were much more promising than those observed when NAC was administered following irradiation; especially in case of the apoptotic changes. In conclusion, NAC played a neuro-protective role rather than a corrective one, suggesting a sort of an “off-label use" for NAC as a radio-protector against irradiation bystander effects on non-tumor brain tissues.