Neonatal necrotizing enterocolitis (NEC) is a life-threatening intestinal disease in neonates and the leading cause of mortality in gastrointestinal diseases in premature infants. The etiology of NEC is multifactorial, including preterm delivery, artificial feeding, intestinal flora alteration, infection and genetic factors, but its exact pathogenesis is not fully understood. The elevation of Toll-like receptor 4 (TLR4 ) expression in intestinal cells of premature infants is considered to be a key factor involved in the occurrence of NEC. Considering the increasing findings emerged upon the role of TLR 4 in the pathogenesis of NEC, this review mainly discusses the related new research progress and the potential therapeutic approaches for NEC.