The post-anesthesia care unit (PACU) length of stay is an important perioperative efficiency metric. The aim of this study was to develop machine learning models to predict ambulatory surgery patients at risk for prolonged PACU length of stay - using only pre-operatively identified factors - and then to simulate the effectiveness in reducing the need for after-hours PACU staffing. Several machine learning classifier models were built to predict prolonged PACU length of stay (defined as PACU stay ≥ 3 hours) on a training set. A case resequencing exercise was then performed on the test set, in which historic cases were re-sequenced based on the predicted risk for prolonged PACU length of stay. The frequency of patients remaining in the PACU after-hours (≥ 7:00 pm) were compared between the simulated operating days versus actual operating room days. There were 10,928 ambulatory surgical patients included in the analysis, of which 580 (5.31%) had a PACU length of stay ≥ 3 hours. XGBoost with SMOTE performed the best (AUC = 0.712). The case resequencing exercise utilizing the XGBoost model resulted in an over three-fold improvement in the number of days in which patients would be in the PACU past 7pm as compared with historic performance (41% versus 12%, P<0.0001). Predictive models using preoperative patient characteristics may allow for optimized case sequencing, which may mitigate the effects of prolonged PACU lengths of stay on after-hours staffing utilization.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10916-023-01966-9.