Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues,including the CNS ,irrespective of the presence of the viral RNA. Here,we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive func- tion, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependentengulfment ofsynap- ses. Genetic of pharmacological blockage of Toll-likereceptor4(TLR4) signaling protects animal against synapse elimination and memory dysfunction induced y Spike braininfusion. Accordingly,in a cohort of 86 patients who recovered from mildCOVID-19, the genotype GGTLR4-2604G>A(rs10759931)is associated with poor cognitive outcome.These results identify TLR4 as a key target to investigate the long-termcogni- tive dysfunctio nafte rCOVID-19 infection in humans and rodents.