Ischemic stroke is the most common, fatal and disabling disease of the central nervous system. Despite considerable progress in primary prevention, diagnostic testing, and treatment, the increased incidence of stroke has created a serious public health problem worldwide, with a significant impact on the families and societies of those affected. The study of ketogenic (KD) and calorie-restricted (CR) diets has become a hot topic of research and is gradually penetrating into the daily diet. Although there are many studies on the neuroprotective mechanisms of KD and CR, the duration of the interventions is relatively short and the mechanisms are not well understood. Therefore, whether long-term ketogenic diet and calorie-restricted diet treatment can improve the resistance to ischemic-hypoxic injury in healthy aged C57 mice, and the mechanism still deserves further investigation. Young 6-month-old mice were randomly divided into KD, CR and control groups, and an ischemic stroke model of endothelin-1 was established on the basis of dietary intervention for 15 months, and the mechanism was explored based on bioinformatics method. Our results confirm that long-term dietary treatment of KD and CR reduces neuronal death in infarct foci and improves neuronal resistance to ischemia and hypoxia by upregulating UBR4 to inhibit the CamkII/TAK1/JNK signaling pathway, then suppress oxidative stress, thus acting as a neuroprotective agent. To be conclusive, ketogenic and calorie-restricted diets have a significant effect on ischemic stroke, but well-designed future clinical studies are necessary to provide solid evidence on this topic.