Background: The National Disaster Medical System (NDMS) is a network of U.S. hospitals that voluntarily agree to provide definitive medical care for military casualties, expanding medical capacity beyond Department of Defense (DOD) medical treatment facilities to Veterans Affairs (VA) medical centers and civilian hospitals. Under an NDMS activation, the receipt, distribution, and definitive care of combat casualties in the Continental U.S. (CONUS) will require stakeholders, processes, and resources at the federal, regional, state, and local levels. To improve medical surge readiness and health outcomes for combat casualties during a large-scale combat operation (LSCO), the NDMS Pilot Program developed a systems-level model of dynamic patient and staff distribution and movement across the nation under multiple LSCO scenarios. Methods: A dynamic event-driven simulation model of the NDMS was developed using doctrine, policy, and data related to the NDMS mission. The model was populated with health facility locations, affiliations, and capacities (e.g., personnel, bed counts) that are signatories of the NDMS memoranda of agreement; casualty numbers and injury/illness types; patient recovery schedules; and transportation assets. Diverse casualty distribution scenarios were evaluated to understand the flow of combat casualties through the NDMS with respect to the U.S. Transportation Command’s CONUS Patient Distribution Plan (CPDP) as well as alternative casualty distribution logistics. Because patient flow from outside CONUS (OCONUS) sites to the CONUS aeromedical evacuation hubs (‘hubs’) is a function of total military logistics, the model assumes optimizing patient distribution begins upon casualty receipt at a hub. Results: We constructed a flexible and extensible model that accounts for several intricacies associated with the distribution and treatment of patients across NDMS-associated facilities. Initial patient reception, based on the CPDP, occurs at three hubs (namely, Travis Air Force Base near Sacramento, California; Kelly Air Field near San Antonio, Texas; and Joint Base Andrews near Washington, D.C.) with patients distributed to medical facilities within a 75-mile radius. The model, as constructed, easily accepts additional patient receiving hubs/spokes and hospitals, allowing instantiation up to a full NDMS configuration that incorporates all 65 CONUS Federal Coordination Centers’ locations and >1700 DOD, VA, and civilian hospitals. Patient casualty type distributions can be adjusted, along with definitive care requirements (e.g., bed types, stay lengths, and number of treatment stages). As the NDMS assumes a LSCO generating a potential 1,000 combat casualties to the U.S. per day for 100 days, model development balanced appropriate abstraction to handle this patient load with a reasonable run time. These features reduce the overhead associated with defining and evaluating a particular scenario, allowing for rapid testing of wide-ranging potential NDMS mission scenarios. Conclusion: Orchestrating the movement and distribution of patients and staff during a LSCO is a significant coordination challenge across the military and civilian healthcare sectors. This model permits the identification of capability and capacity limitations in the NDMS, evaluation of downstream effects of proposed solutions, and development of recommendations that optimize courses of action for the federal interagency. In turn, improved planning and preparedness will result in better health outcomes for combat casualties and civilians.