Neonatal shock and necrotizing enterocolitis (NEC) are leading causes of morbidity and mortality in premature infants. NEC is a life-threatening gastrointestinal illness, the precise etiology of which is not well understood, but is characterized by an immaturity of the intestinal barrier, altered function of the adaptive immune system, and intestinal dysbiosis. The complexities of NEC and shock in the neonatal population necessitate relevant clinical modeling using newborn animals that mimic the disease in human neonates to better elucidate the pathogenesis and provide an opportunity for the discovery of potential therapeutics. A wide variety of animal species-including rats, mice, piglets, and primates-have been used in developing experimental models of neonatal diseases such as NEC and shock. This review aims to highlight the immunologic differences in neonates compared with adults and provide an assessment of the advantages and drawbacks of established animal models of both NEC and shock using enteral or intraperitoneal induction of bacterial pathogens. The selection of a model has benefits unique to each type of animal species and provides individual opportunities for the development of targeted therapies. This review discusses the clinical and physiologic relevance of animal models and the insight they contribute to the complexities of the specific neonatal diseases: NEC and shock.