Neonatal abstinence syndrome (NAS) is a growing problem in the United States, related to increased maternal substance use and abuse, and a set of drug withdrawal symptoms that can affect the central nervous system and gastrointestinal and respiratory systems in the newborn when separated from the placenta at birth. Infants with NAS often require a significant length of stay in the neonatal intensive care unit (NICU). Pharmacologic treatments and physician-directed interventions are well researched, but nursing-specific interventions and recommendations are lacking. A thorough review and analysis of the literature and interviews with neonatal experts guided the development of a nursing clinical practice guideline for infants with NAS in a level IV NICU. Recommended nursing-specific interventions include methods for maternal drug-use identification, initiation and timing of the Finnegan Scoring System to monitor withdrawal symptoms, and bedside interventions to lessen the drug-withdrawal symptoms in the newborn with NAS.