Necrotizing enterocolitis (NEC) is a gastrointestinal emergency that leads to inflammation and intestinal necrosis. Although probiotics can decrease the incidence of NEC, consistent recommendations for probiotic administration to very low-birth-weight (VLBW) neonates are lacking. Here, the best available evidence is reviewed and a practice guideline for probiotic administrations to VLBW neonates is described. A systematic review was conducted using MEDLINE and EMBASE, and the strength of evidence was classified using the Centre for Evidence-Based Medicine classification schema. Probiotics for VLBW neonates may decrease the incidence of NEC. Providers may choose to give probiotics to VLBW neonates at risk of acquiring NEC in facilities with a high NEC incidence. Clinicians must monitor infants for possible adverse effects. Contraindications for probiotic use include extremely low birth weight, clinical instability, abnormal abdominal examination, the presence of congenital abnormalities, post-NEC, stage III asphyxia, and umbilical catheters.