Following a major disaster, hospitals must promptly rearrange their organization and treatment procedures to deal with the sudden arrival of a high number of injured people to minimize morbidity and mortality. These procedural changes are included in emergency plans that hospitals are required to define. Nonetheless, procedures followed in emergency situations may not always be consistent with those planned during “peace time”, and their effectiveness is tested only in case of a disaster. For these reasons, defining a model that simulates the patient flow through the hospital would prove crucial to preventively test the response capacity in case of a disaster. In this paper, the analysis of different emergency plans, interviews with healthcare professionals and an extensive literature review are used to derive two Discrete-Event Simulation models of a hospital digital twin, representing operations in routine and post-earthquake conditions. The two models are defined by balancing the need to represent a complex system with sufficient accuracy, the limitations posed by data availability and the multiplicity of outcomes of a patient treatment. The models are general in their definition, and their potentiality is shown through the application to a reference case study representative of a small hospital in Central Italy.