COVID-19 pandemic affected the global population in an unprecedented scale, with long-term consequences of SARS CoV-2 infection now emerging as a serious concern. Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. Here we demonstrated that brain exposure to SARS-CoV-2 spike (S) protein through its infusion into the lateral ventricle of adult mice induced late cognitive impairment, hippocampal synapse loss, and microglial engulfment of presynaptic terminals. Additionally, TLR4 blockage prevented Sassociated detrimental effects on memory in mice and TLR4 single nucleotide polymorphism (SNP) rs10759931 was associated with late cognitive outcome in mild COVID-19-recovered patients. Collectively, these findings indicate that S protein directly impacts the brain and identify TLR4 as a key target to prevent cognitive dysfunction. To our knowledge, this is the first animal model that recapitulates postCOVID cognitive impairment, opening new avenues for developing new strategies to prevent or treat the neurological outcomes of COVID-19.