Preterm birth interrupts the development of the human gastrointestinal tract, resulting in an immature permeable gut barrier with increased risk of intestinal pathology, such as necrotizing enterocolitis (NEC). The gut microbiota metabolize dietary components into bioactive metabolites that play a crucial role in maintaining intestinal homeostasis. While the roles of microbial metabolites have been studied in relation to adult gastrointestinal diseases, their specific impact on preterm infants remains unexplored. This review aims to identify how microbial metabolites interact with the developing gut barrier in preterm infants, focusing on their role in gut inflammation and NEC. Metabolites include short-chain and conjugated fatty acids, indole derivatives, bile acids, polyamines, and polyphenolic compounds. An overview of the unique features of the premature gut barrier physiology is provided, including perinatal developmental changes in cellular structure, cell junctions, and the gut microbiome. Potential benefits and molecular mechanisms of microbial metabolites in the premature intestine and environmental factors responsible for NEC are discussed. In summary, microbiome-derived mediators have the potential to strengthen preterm gut barrier integrity and alleviate inflammatory stress. Further research may reveal clinically relevant preventative or therapeutic treatment targets for NEC in preterm infants.