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Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNβ before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates. Viral lung infections are the number one reason for hospitalization of children under the age of 5 and are a major public health concern. Premature babies, or those born before 37 weeks gestation, are particularly susceptible to viral infections, but exact mechanisms for this susceptibility have not been determined. Here, using a pre-clinical infant mouse model of influenza virus infection, we have found increased neonatal susceptibility to respiratory viral infection compared to adults, and we demonstrate that a probiotic administered intranasally prior to infection provides dramatic protection to infant mice by inducing production of a key anti-viral cytokine, type I interferons. [ABSTRACT FROM AUTHOR]