Stroke is currently the second leading cause of death worldwide, and it accounts for approximately 3-7% of total healthcare expenditures worldwide. Cerebral ischemic stroke has known to cause irreversible damage to the brain by variety mechanisms of excitotoxicity and apoptosis within hours after hypoxic challenge. Recent evidence suggests that a ketogenic diet may reduce infarct volume and neuronal damage in ischemic stroke models. However, the connection between physiological changes induced by the diet with the pathological alterations in hypoxic susceptibility remains unclear. In this research, we expanded upon preliminary observations suggesting neuroprotection against ischemic stroke due to ketogenic diet, which correlates with changes in gut microbiota and serum metabolite levels. We aim to investigate the potential role of Trace amine-associated receptor 1 (TAAR1) in mediating this protective effect. By using the photothrombotic stroke model to evaluate the role of TAAR1 in the neuroprotective effects of a ketogenic diet. The study involved various methods, including fecal microbiota transplantation, regional silencing of TAAR1, bacterial colonization, and pharmacological activation of TAAR1 receptors, to confirm TAAR1's involvement in the diet's neuroprotective mechanism. Meanwhile, via both in vitro oxygen-deprivation hypoxic models and in vivo ischemic stroke surgery, we identified the molecular mechanisms through which TAAR1 offers protection against hypoxic challenges. Furthermore, by analyzing fresh platelets from both mouse and human subjects, we explored how ketogenic diet and TAAR1 receptor activation affect platelet function. Our findings suggest a promising therapeutic strategy for reducing irreversible neurological damage caused by ischemic stroke, potentially through the activation of TAAR1.