Although radiation therapy can be effective against cancer, potential damage to normal tissues limits the amount that can be safely administered. In the central nervous system (CNS), radiation damage to normal tissues is associated with cognitive impairments. Chronic oxidative stress, neuroinflammation, suppressed hippocampal neurogenesis, and down regulation of the brain-derived neurotrophic factor (BDNF) have been identified as the causes for cognitive impairments following radiation therapy of the CNS. Based on these mechanisms, we tested two experimental drugs, each targeting a different pathway, for their ability to preserve normal tissue functions in experimental animals following cranial irradiation. The Mn porphyrin (MnP)-based redox active drug, MnTnBuOE-2-PyP5+ (MnBuOE), is able to cross the blood brain barrier and has been shown to protect normal tissues from radiation damage. Administration of MnBuOE for one week before cranial irradiation and continued for one week afterwards supported production and long-term survival of newborn neurons in the hippocampal dentate gyrus. However, prolonged administration of MnBuOE following cranial irradiation did not increase the efficacy further, suggesting the best therapeutic window for redox active drugs is centered around the time of irradiation. The small flavonoid compound 7,8-dihydroxyflavone (7,8-DHF) has been shown to activate the high affinity BDNF receptor, TrkB, and enhance dendrite outgrowth and neuronal survival. Chronic treatment with 7,8-DHF following cranial irradiation significantly restored spatial, contextual, and working memory, and this was achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity during the recovery phase following cranial irradiation. Given the different biological effects of the two experimental drugs, strategic use during their optimal therapeutic windows before and after cranial radiation therapy may achieve the best efficacy in preserving normal tissue functions.