BACKGROUND: Patient safety in the intensive care unit (ICU) is one of the most critical issues, and unplanned extubation (UE) is considered the most adverse event for patient safety. Prevention and early detection of such an event is an essential but difficult component of quality care. OBJECTIVE: This study aimed to develop and validate prediction models for UE in ICU patients using machine learning. METHODS: This study was conducted in an academic tertiary hospital in Seoul, Republic of Korea. The hospital had approximately 2000 inpatient beds and 120 ICU beds. As of January 2019, the hospital had approximately 9000 outpatients on a daily basis. The number of annual ICU admissions was approximately 10,000. We conducted a retrospective study between January 1, 2010, and December 31, 2018. A total of 6914 extubation cases were included. We developed a UE prediction model using machine learning algorithms, which included random forest (RF), logistic regression (LR), artificial neural network (ANN), and support vector machine (SVM). For evaluating the model's performance, we used the area under the receiver operating characteristic curve (AUROC). The sensitivity, specificity, positive predictive value, negative predictive value, and F1 score were also determined for each model. For performance evaluation, we also used a calibration curve, the Brier score, and the integrated calibration index (ICI) to compare different models. The potential clinical usefulness of the best model at the best threshold was assessed through a net benefit approach using a decision curve. RESULTS: Among the 6914 extubation cases, 248 underwent UE. In the UE group, there were more males than females, higher use of physical restraints, and fewer surgeries. The incidence of UE was higher during the night shift as compared to the planned extubation group. The rate of reintubation within 24 hours and hospital mortality were higher in the UE group. The UE prediction algorithm was developed, and the AUROC for RF was 0.787, for LR was 0.762, for ANN was 0.763, and for SVM was 0.740. CONCLUSIONS: We successfully developed and validated machine learning-based prediction models to predict UE in ICU patients using electronic health record data. The best AUROC was 0.787 and the sensitivity was 0.949, which was obtained using the RF algorithm. The RF model was well-calibrated, and the Brier score and ICI were 0.129 and 0.048, respectively. The proposed prediction model uses widely available variables to limit the additional workload on the clinician. Further, this evaluation suggests that the model holds potential for clinical usefulness.