There is significant communication and interdependence among the gut, the microbiome, and the brain during development. Diseases, such as necrotizing enterocolitis (NEC), highlight how injury to the immature gastrointestinal tract leads to long-term neurological consequences, due to vulnerabilities of the brain in the early stages of life. A better understanding of the developing gut–microbiota–brain axis is needed to both prevent and treat the devastating consequences of these disease processes. The gut–microbiota–brain axis is a bidirectional communication pathway that includes metabolic, nervous, endocrine, and immune components. In this review, we discuss gut development, microbiome colonization and maturation, and the interactions that influence neurodevelopment in the context of NEC. We describe the components of the gut–brain axis and how the microbiome is an integral member of this relationship. Finally, we explore how derangements within the microbiome and gut–microbiota–brain axis affect the normal development and function of the other systems and long-term neurodevelopmental consequences for patients.