Background: Pulmonary interstitial emphysema (PIE) is a rare pathology characterized by the abnormal and harmful presence of air in the interstitial tissues of the lung. This condition is often related to barotrauma caused by mechanical ventilation, but it can be exceptionally seen in healthy infants. The main causes of PIE are respiratory distress syndrome (RDS), mechanical ventilation or positive pressure ventilation, prematurity, meconium aspiration syndrome, pulmonary infection, amniotic fluid aspiration, and incorrect endotracheal tube placement. To date, there is no standard treatment for PIE, based on the clinical and localization of PIE conservative and non-- conservative therapies are described. Methods: We describe a case of a very premature infant with severe respiratory failure secondary to RDS and unilateral left sided PIE with lung herniation treated with conservative therapy like selective intubation, steroid therapy, lateral position, and lastly, oxygen supplementation without ventilatory assistance. Furthermore, we have carried out a systematic literature review for the past 15 years (2007-2022). A systematic review, using an evidence-based algorithmic approach, was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Our search, after the selection, produced a total of 24 articles, which were revised. Conclusion: In our case oxygen supplementation without ventilatory assistance resulted in successful resolution of the left PIE. Discontinuation of ventilatory care played a crucial role. Considering the management reported in literature, our aim is to perform a systematic literature review by adding our experience to the available knowledge on therapy for unilateral PIE.