Extubation failure (EF) is a significant concern in mechanically ventilated newborns, and predicting its occurrence is an ongoing area of research. To investigate the predictors of EF in newborns undergoing planned extubation, we conducted a systematic review and meta-analysis. A systematic literature search was conducted in PubMed, Web of Science, Embase, and Cochrane Library for studies published in English from the inception of each database to March 2023. The PRISMA guidelines were followed in all phases of this systematic review. The Risk of Bias Assessment for Nonrandomized Studies tool was used to assess methodological quality. Thirty-four studies were included, 10 of which were overall low risk of bias, 15 of moderate risk of bias, and 9 of high risk of bias. The studies reported 43 possible predictors in six broad categories (intrinsic factors; maternal factors; diseases and adverse conditions of the newborn; treatment of the newborn; characteristics before and after extubation; and clinical scores and composite indicators). Through a qualitative synthesis of 43 predictors and a quantitative meta-analysis of 19 factors, we identified five definite factors, eight possible factors, and 22 unclear factors related to EF. Definite factors included gestational age, sepsis, pre-extubation pH, pre-extubation FiO2, and respiratory severity score. Possible factors included age at extubation, anemia, inotropic use, mean airway pressure, pre-extubation PCO2, mechanical ventilation duration, Apgar score, and spontaneous breathing trial. With only a few high-quality studies currently available, well-designed and more extensive prospective studies investigating the predictors affecting EF are still needed. In the future, it will be important to explore the possibility of combining multiple predictors or assessment tools to enhance the accuracy of predicting extubation outcomes in clinical practice.© 2023. Società Italiana di Pediatria.