OBJECTIVES Necrotizing enterocolitis (NEC) is a severe intestinal inflammatory disease and a leading cause of morbidity and mortality in NICUs. Management of NEC is variable because of the lack of evidence-based recommendations. It is widely accepted that standardization of patient care leads to improved outcomes. This quality improvement project aimed to decrease variation in the evaluation and management of NEC in a Level IV NICU. METHODS A multidisciplinary team investigated institutional variation in NEC management and developed a standardized guideline and electronic medical record tools to assist in evaluation and management. Retrospective baseline data were collected for 2 years previously and prospectively for 3.5 years after interventions. Outcomes included the ratio of observed-to-expected days of antibiotics and nil per os (NPO) on the basis of the novel guidelines and the percentage of cases treated with piperacillin/tazobactam. Balancing measures were death, surgery, and antifungal use. RESULTS Over 5.5 years, there were 124 evaluations for NEC. Special cause variation was noted in the observed-to-expected antibiotic and NPO days ratios, decreasing from 1.94 to 1.18 and 1.69 to 1.14, respectively. Piperacillin/tazobactam utilization increased from 30% to 91%. There were no increases in antifungal use, surgery, or death. CONCLUSIONS Variation in evaluation and management of NEC decreased after initiation of a guideline and supporting electronic medical record tools, with fewer antibiotic and NPO days without an increase in morbidity or mortality. A quality improvement approach can benefit patients and decrease variability, even in diseases with limited evidence-based standards.