Stroke is a serious acute cerebrovascular disease. Microglia-mediated inflammatory response plays an important role, but its mechanism is unclear. Neural stem cells have neuroprotective effects by releasing exosomes in paracrine mode. TAK-242 is a specific inhibitor of TLR4, which can inhibit the activation of TLR4/NF-ĸB pathway. The aim of this study was to explore the regulatory mechanism of Neural stem cell-derived exosomes (NSC-Exos) in promoting the repair of damaged rat nerve function and inhibiting inflammatory response. Right t-MCAO model was constructed by blocking the right middle cerebral artery one day after rat lateral ventricle was injected with TAK-242 inhibitor. Three days after the transplant, cognitive function was assessed using a neurological deficit score; The brain injury was assessed histopathologically; Immunohistochemistry and immuno-fluorescence histochemistry were used to detect microglia and inflammatory factors. RT-qPCR and Western blotting have been detected in molecules of TLR4/NF-κB pathway. The results showed that the neural function of t-MCAO model rats was impaired, the brain histopathological injury was aggravated, the microglia secreted pro-inflammatory factor and CD86+/Iba1+ positive cells increased, and the expression of TLR4/NF-κB related signaling molecules increased. After intervention of NSC-Exos, the brain histopathological injury was reduced, the number of CD206+/Iba1+positive cells and anti-inflammatory factor and was increased, and the expression of TLR4/NF-κB related molecules was decreased. More interestingly, inhibition of TAK-242 partially reversed these outcomes after NSC-Exos transplantation. These results suggest that NSC-Exos improves the microglia-mediated inflammatory response in rats with ischemic brain injury, which may be related to the regulation of TLR4/NF-κB pathway.