This article presents an hybrid and hierarchical model in which two modeling and simulation approaches, discrete event system specification simulation (DEVS) and semantic technologies, were used together in order to help in the analysis of a major healthcare problem, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Indeed, the complexity of the SARS-CoV-2 replication process, and the range of hierarchical scales over which it interacts with cellular components (extending from genomic and transcriptomic to proteomic and metabolomic scales), and the intricate way in which they are interwoven, make its understanding very challenging. It is therefore crucial to model the different scales of the replication process, by taking into account all interactions with the infected cell. By combining the advantages of both DEVS simulation and ontological modeling, we propose a hierarchical ontology-based DEVS simulation model of the SARS-CoV-2 viral replication at both the micro-molecular (proteomic and metabolomic) and macro-molecular (genomic and transcriptomic) scales. First, we demonstrate the usefulness of combining DEVS simulation and semantic technologies in a common modeling framework to face the complexity of the SARS-CoV-2 viral replication at different scales. Second, the modeling and simulation of the SARS-CoV-2 replication process on different levels provide valuable information on the different stages of the virus’s life cycle and lays the foundation for a system to anticipate future mutations selected by the virus.