Rapid diagnosis of sudden, unexpected, and potentially fatal complications in the neonatal intensive care unit (NICU) is essential for the initiation of prompt and life-saving management. Point-of-care ultrasound (POCUS) protocols are widely used in adult emergency situations to diagnose and guide treatment, but none has been specifically developed for the neonate. We propose a targeted diagnostic ultrasound protocol for the suddenly decompensating infant in the NICU for rapid screening for the most common life-threatening complications needing immediate attention. We integrated current knowledge on the use of POCUS for diagnosis of the most critical neonatal complications into the “SAFE-R protocol” (Sonographic Assessment of liFe-threatening Emergencies – Revised). The ultrasound algorithm was evaluated at the bedside for suitability and ease of use. Main features of SAFE-R are the use of standardized ultrasound points and a simple one-probe rule-in/rule-out approach. The flowchart is designed by order of urgency and priority is given to treatable causes. Hence, ruling out cardiac tamponade is the first step in the decision tree, followed by pneumothorax, pleural effusion, then acute critical aortic occlusion, acute abdominal complications, and severe intraventricular hemorrhage.Conclusion: SAFE-R is the first ultrasound algorithm specifically conceived for use in the NICU to screen for the most common urgent neonatal complications leading to sudden deterioration, thereby providing critical information within minutes. The simplified and rapid approach is designed for the neonatologist and is easy to learn and quick to perform. What is Known: • The fields of neonatal and pediatric critical care are undergoing a transformation with the adoption of POCUS and the recent publication of the first international guidelines on POCUS for critically ill children and neonates. • Targeted emergency ultrasound protocols are widely used in adult emergency and critical care medicine, but specific and adapted ultrasound algorithms are lacking for the pediatric and neonatal population. What is New: • We propose the first targeted ultrasound protocol specifically designed for the suddenly decompensating infant in the NICU for rapid screening of the most common life-threatening complications needing immediate attention. • The SAFE-R ultrasound algorithm integrates current knowledge on ultrasound diagnosis of the most critical neonatal complications into a simple and easy-to-perform emergency scanning protocol aimed to guide initial management and resuscitation efforts.