Mechanical ventilation is one of the most commonly used treatments in neonatology. Prolonged mechanical ventilation is associated with deleterious outcomes. To reduce the ventilation duration, weaning protocols have been developed to achieve extubation in adult and pediatric care in a safe and uniform manner. We performed a systematic review to obtain all available evidence on the effect of protocolized versus nonprotocolized weaning on the duration of invasive mechanical ventilation in critically ill neonates. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Web of Science, and the International Clinical Trial Registry Platform were searched until January 2018. Quantitative and qualitative studies involving neonates that investigated or described protocolized versus nonprotocolized weaning were included. Primary outcome was the difference in weaning duration. A total of 2099 potentially relevant articles were retrieved. Three studies met the inclusion criteria. Of 2 of these, the separate neonatal data could not be obtained. Only one retrospective study was included for this review. This reported a decrease in the mean weaning time from 18 to 5 and 6 days, respectively. There is no robust evidence in the literature to support or disprove the use of a weaning protocol in critically ill neonates.