Remote ischemic postconditioning (RIPC) has been proven to be a promising protective method for brain damage caused by transient focal ischemia/reperfusion (I/R) injury. However, the underlying mechanism of RIPC remains elusive. To address whether RIPC protects against brain damage by regulating TLR4 and the NF-κB pathway, focal I/R rat (SD) model induced by 1 h transient middle cerebral artery occlusion was used in this study. RIPC treatment was generated by three cycles of 10 min occlusion and 10 min release of the bilateral hind femoral arteries. The Garcia JH score was used to evaluate neurobehavioral function and triphenyltetrazolium chloride staining was used to estimate the infarct size of the brain. The expression levels of TLR4 and NF-κB were determined by quantitative PCR and immunohistochemistry. The results showed that RIPC treatment significantly improved neurological deficits and decreased infarct volume. Furthermore, it also inhibited the overexpression of TLR4 and NF-κB induced by middle cerebral artery occlusion reperfusion. Thus, we suggested that RIPC might protect ischemic brain against I/R injury in rats by suppressing the TLR4/NF-кB pathway.