Background and aims Preterm birth and infections account for the majority of early childhood morbidity. Neonatal sepsis remains a major clinical and societal burden due to associated neurodevelopmental disturbances. Milk contains several immunologically active compounds and may support infection resistance. Using a novel preterm piglet model of bloodstream infection, we hypothesized that early enteral milk feeding supports resistance against sepsis and neuroinflammation. Methods Forty cesarean born preterm piglets were administered saline (CON) or Staphylococcus epidermidis (SE, 109 CFU/kg) systemically within 6 hours of birth and given total parenteral nutrition (CON-TPN, n=11; SE-TPN, n=15) or enteral nutrition (SE-ENT, n=14, 9 ml/kg/3h cow’s colostrum). After 24 hours, we recorded bacteriology, hematology, hemodynamics, thromboelastographies (TEGs), and acid–base balance. Furthermore, in vivo blood-cerebrospinal fluid (CSF) barrier permeability, CSF leukocyte count, microglia numbers and brain innate immune gene expression were assessed. Results ENT-SE pigs had fewer bacteria than TPN-SE in blood and CSF (both p<0.05), and physical activity levels, blood pressure, blood lactate and acidity were similar to CON-TPN, while TPN-SE pigs showed decreased physical activity, blood pressure and blood pH, and increased lactate (all p<0.05). Lymphopenia, thrombocytopenia and procoagulant TEG profiles were observed in both SE-infected groups. In vivo blood-CSF barrier permeability and CSF leukocytes were lower in ENT-SE than TPN-SE pigs (both p<0.05). Moreover, the ENT treatment downregulated several immune-related genes in the brain, while microglia numbers were increased in both SE-infected groups. Conclusions Using a newly established clinically relevant animal model of neonatal bloodstream infection, we show that early enteral feeding confers resistance against sepsis and neuroinflammation