Gastrointestinal infections caused by Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) remain a major health problem for neonates and young infants worldwide. A better understanding of the mechanisms responsible for disease development and progression during the postnatal period is crucial to improve therapeutic options. Here, using our murine neonatal Salmonella infection model, we analysed the gene, protein and metabolic expression profiles of S. Typhimurium-infected and healthy age-matched wild type and gene-deficient newborn mice. Those analyses revealed alterations of the proliferative and metabolic activities as well as of the antimicrobial peptide repertoire of epithelial cells in infected animals. Several target genes exhibited expression levels comparable to those usually observed in more mature animals. Those alterations were not observed in infected newborn mice lacking MyD88 signalling in their hematopoietic cell compartment. Stimulation of 3D intestinal organoids with various cytokines produced by intestinal immune cells could in part recapitulate the phenotype. Together, our results suggest that S. Typhimurium infection induces an accelerated maturation of the newborn small intestinal epithelium via an immune cell-mediated mechanism. Our work is expected to gain further insight into the short- and long-term consequences of neonatal enteric infections on intestinal homeostasis and disease susceptibility. Additionally, our results might identify therapeutic targets to improve the clinical outcome of infants upon gastrointestinal infection.