Severe bacterial infections affect more than 19 million people each year. With improved treatment strategies, more and more patients survive such severe bacterial infections. However, the majority of these survivors develop cognitive impairment and mental health problems. The pathogenesis of infection-induced cognitive impairment may include vascular injuries and neuro-inflammation, which eventually leads to neuron dysfunction. However, the mechanisms that promote cognitive impairment post infection remain largely unknown. We observed that mice exhibit hippocampus-dependent memory impairment post infection using a contextual fear conditioning (CFC) test. We also observed pathological neuron dysfunction in the form of decreased postsynaptic density protein (PSD)-95 expression, and neuronal dendritic spine density post infection. To understand the mechanisms underlining cognitive impairment post infection, we focused on long noncoding RNA (lncRNA) expression levels in the brain, as they are important regulators of gene expression. We found that lncRNA Nuclear Enriched Abundant Transcript 1 (Neat1) levels were significantly increased in hippocampal neurons after infection. Accordingly, knockdown of Neat1 with antisense oligonucleotide Gapmers in primary neurons upregulated PSD-95 levels and increased neuronal dendritic spine density. Neat1 knockout mice exhibited increased PSD-95 levels, dendritic spine density, and mitigated infection-induced memory impairment. Intriguingly, administration of Neat1 Gapmers in vivo via intravenous injection suppressed Neat1 levels, increased PSD-95 levels in brain tissue, increased dendritic spine density in neurons, and mitigated cognitive impairment in an animal model of infection. These data provide the first evidence of a cause-effect relationship between increased Neat1 levels and cognitive impairment post infection.