Neonatal intensive care units (NICUs) greatly expand the use of technology. There is a need to accurately diagnose discomfort, pain, and complications, such as sepsis, mainly before they occur. While specific treatments are possible, they are often time-consuming, invasive, or painful, with detrimental effects for the development of the infant. In the last 40 years, heart rate variability (HRV) has emerged as a non-invasive measurement to monitor newborns and infants, but it still is underused. Hence, the present paper aims to review the utility of HRV in neonatology and the instruments available to assess it, showing how HRV could be an innovative tool in the years to come. When continuously monitored, HRV could help assess the baby’s overall wellbeing and neurological development to detect stress-/pain-related behaviors or pathological conditions, such as respiratory distress syndrome and hyperbilirubinemia, to address when to perform procedures to reduce the baby’s stress/pain and interventions, such as therapeutic hypothermia, and to avoid severe complications, such as sepsis and necrotizing enterocolitis, thus reducing mortality. Based on literature and previous experiences, the first step to efficiently introduce HRV in the NICUs could consist in a monitoring system that uses photoplethysmography, which is low-cost and non-invasive, and displays one or a few metrics with good clinical utility. However, to fully harness HRV clinical potential and to greatly improve neonatal care, the monitoring systems will have to rely on modern bioinformatics (machine learning and artificial intelligence algorithms), which could easily integrate infant’s HRV metrics, vital signs, and especially past history, thus elaborating models capable to efficiently monitor and predict the infant’s clinical conditions. For this reason, hospitals and institutions will have to establish tight collaborations between the obstetric, neonatal, and pediatric departments: this way, healthcare would truly improve in every stage of the perinatal period (from conception to the first years of life), since information about patients’ health would flow freely among different professionals, and high-quality research could be performed integrating the data recorded in those departments.