Inhaled nitric oxide (INO) is a colorless, odorless gas that is also a potent pulmonary vasodilator. When given via the inhaled route it is a selective pulmonary vasodilator. INO is approved by the United States Food and Drug Administration (FDA) for the treatment of term and near-term neonates with hypoxemic respiratory failure associated with clinical or echocardiographic evidence of pulmonary arterial hypertension. A systematic review of the literature was conducted with the intention of making recommendations related to the clinical use of INO for its FDA-approved indication. Specifically, we wrote these evidence-based clinical practice guidelines to address the following questions: (1) What is the evidence for labeled use? (2) What are the specific indications for INO for neonates with acute hypoxemic respiratory failure? (3) Does the use of INO impact oxygenation, mortality, or utilization of extracorporeal membrane oxygenation (ECMO)? (4) Does INO affect long-term outcomes? (5) Is INO cost-effective therapy? (6) How is the appropriate dosing regimen and dose response to INO established? (7) How is the dose of INO titrated and weaned? (8) Which INO delivery system should be used? (9) How should INO be implemented with different respiratory support devices? (10) What adverse effects of INO should be monitored, and at what frequency? (11) What physiologic parameters should be monitored during INO? (12) Is scavenging of gases necessary to protect the caregivers? Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scoring system, 22 recommendations are developed for the use of INO in newborns.