Increasing evidence indicates that many of the health beneficial effects associated with the establishment of a symbiotic gut microbiota are driven by bacterial metabolic by-products. The term “postbiotics” indicates any soluble factor resulting from the metabolic activity of a live bacteria or any released molecule capable of providing health benefits through a direct or indirect mechanism. Alterations in preterm gut colonization associated with the intestinal barrier immaturity and the increased reactivity of the intestinal mucosa to colonizing bacteria have been implicated in the pathogenesis of necrotizing enterocolitis. Recent advances in the comprehension of the postbiotic biological effects and related mechanisms, some of them reviewed here, indicate that postbiotics may be a promising effective preventive strategy against necrotizing enterocolitis while avoiding the risk of administering live microorganisms to preterm infants that could translocate and cause infection. However, data from trials investigating the efficacy of postbiotics for the prevention of necrotizing enterocolitis in preterm infants are needed, and issues regarding their optimal regimen and start and duration of treatment need to be addressed.