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Recent advances in artificial intelligence (AI) and machine learning (ML) enable targeted optimization of emergency department (ED) operations. We examine how reworking an ED’s vertical processing pathway (VPP) using AI- and ML-driven recommendations affected patient throughput. Methods: We trained a non-linear ML model using triage data from 49,350 ED encounters to generate a personalized risk score that predicted whether an incoming patient is suitable for vertical processing. This model was integrated into a stochastic patient flow framework using queueing theory to derive an optimized VPP design. The resulting protocol prioritized a vertical assessment for patients with Emergency Severity Index (ESI) scores of 4 and 5, as well as 3 when the chief complaints involved skin, urinary, or eye issues. In periods of ED saturation, our data-driven protocol suggested that any waiting room patient should become VPP eligible. We implemented this protocol during a 13-week prospective trial and evaluated its effect on ED performance using before-and-after data. Results: Implementation of the optimized VPP protocol reduced the average ED length of stay (LOS) by 10.75 min (4.15%). Adjusted analyses controlling for potential confounders during the study period estimated a LOS reduction between 7.5 and 11.9 min (2.89% and 4.60%, respectively). No adverse effects were observed in the quality metrics, including 72 h ED revisit or hospitalization rates. Conclusions: A personalized, data-driven VPP protocol, enabled by ML predictions, significantly improved the ED throughput while preserving care quality. Unlike standard fast-track systems, this approach adapts to ED saturation and patient acuity. The methodology is customizable to patient populations and ED operational characteristics, supporting personalized patient flow optimization across diverse emergency care settings.