Background and Purpose: The epidemic use of opioids is negatively influencing the health of the American people. Pregnant women and their unborn babies have not escaped the ravages of substance use. A dramatic increase in maternal opioid use has led to an increasing number of infants experiencing withdrawal symptoms known as neonatal abstinence syndrome (NAS). The purpose of this article is to highlight best practice for the management of infants with opioid withdrawal. Review of Protocols and Treatments: Review of available protocols and treatments revealed wide variation in the treatment of NAS and little use of standardized guidelines or protocols, despite current recommendations of the American Academy of Pediatrics. There is supporting evidence showing that the use of standardized protocols reduces the length of treatment and enhances outcomes in the neonatal population. Evidence-Based Recommendations: Evidence-based strategies to address gaps in practice include developing strong protocols to identify infants at risk and implementing standardized plans when treating NAS. Consistent assessment, initial treatment with nonpharmacologic measures, and conservative use of pharmacologic agents are important elements to an NAS treatment protocol. Conclusions and Implications: In evaluating the current literature for best practice in the management of the newborn with opioid withdrawal, it is clear that evidence-based standardized protocols need to be in place for the best treatment of the mother-infant dyad, caring for both the infants with NAS as well as the mothers with opioid use disorder.