In this study, we studied a late-stage TBI model (4–8 weeks) with NLRP3-knockout (KO) and wild-type (WT) mice and conducted behavioral tests, field excitatory postsynaptic potential (fEPSP) recordings and molecular biology analyses to confirm that the continuous activation of the NLRP3 inflammasome and elevated HMGB1 are the key causes of TBI-induced cognitive impairment. Here, HMGB1 is linked to Cognitive impairment.