Group A streptococcus (GAS) infection causes a strong inflammatory response associated with cytokine storm which leads to multi-organ failure characterized as streptococcal toxic shock syndrome (STSS). However, little is known about the systemic inflammatory effects of GAS infection on neurodegeneration in the brain. Therefore, we utilized a bioluminescent GAS strain and the reporter mice carrying firefly luciferase under transcriptional control of the NF-κB promoter to concurrently monitor the host immune response and bacterial burden in a single mouse. Interestingly, in addition to the inoculation locus, we additionally detected strong luminescence signals from NF-κB activation in the brain without detectable bacterial signal, suggestion the central inflammation is not mediated by disseminated bacteria. The inflamed brain showed increased expression of GFAP and NADPH oxidase components, displayed greater microglial activation and blood brain-barrier (BBB) disruption. Furthermore, Fluoro-Jade C positive cells were increased in the brain indicating that neurons were undergoing degeneration. Peripheral TNF, which contributes to pathology in brain injury, was elevated in the circulation and the expression of its receptor was also increased in the inflamed brain. Blockage of peripheral TNF effectively decreased brain inflammation and injury, preventing BBB disruption and improving survival. Our studies provide new insight into GAS-induced central inflammation, such as encephalopathy, which can be attenuated by circulating TNF blocking.