Abstract Late-onset neonatal sepsis (LOS) is a bacterial bloodstream infection that occurs during the first two months of life, and remains a significant contributor to neonatal mortality. In addition to the number of clinical challenges these patients face in the short term, neonates who survive LOS can experience a number of long-term adverse outcomes, such as impaired cognitive development. A major obstacle in LOS research remains the lack of an animal model that successfully recapitulates clinical LOS. We have developed a mouse model that replicates the clinical finding that a subset of LOS infections results from enterally-derived pathogens translocating from the intestine. In this model, pups develop sepsis-like disease upon oral gavage of virulent E. coli species. This translocation results in immune cell infiltration and bacterial presence in many peripheral sites, including the meninges. Specifically, we found infiltration of monocytes, and neutrophils into the meninges, along with increased numbers and activation status of both αβ+ and γδ+ T cells. Meningitis could be replicated by LPS alone, suggesting systemic bacterial presence contribute to infiltration into the meninges. Interestingly, mice older than 10 days did not develop meningitis in response to LPS, suggesting neonatal pups are uniquely susceptible to bacterial-initiated meningitis. Furthermore, this meningitis is induced partially by adaptive immune cell components, as no neutrophil or monocyte infiltration was seen in RAG KO mice following LPS injection. This study provides novel insights into the clinical reported complication of meningitis during LOS and suggests a unique contribution of adaptive lymphocytes in the neonate during this systemic infection.