Necrotizing enterocolitis remains a significant cause of morbidity and mortality in very low-birth-weight infants (<1500 g), with current preventive strategies unclear. Scientific evidence has recently emerged, suggesting that probiotics, prebiotics, and synbiotics may effectively and safely alter the premature intestinal microbiota, enhancing a deficient innate immune response and maturing the intestinal barrier to prevent necrotizing enterocolitis development. Currently, formal recommendations do not support routine use of these dietary supplementations for premature infants. Here, we examine how probiotic, prebiotic, and synbiotic preparations physiologically alter the underdeveloped intestinal microbial environment to potentially reduce necrotizing enterocolitis incidence and discuss current evidence that has examined safety and efficacy factors potentially supporting routine use among the premature infant population.