The increasing complexity of current system realities (e.g., pandemics, healthcare, energy transition, process industry 4.0 etc.) would require the evaluation of the actual way systems are modified, often referred with “work as done”, rather than “work as imagined”. The safety of a complex system is one of the emergent properties depending upon the interactions between the system's components and subsystems. This paper is focused on the analysis of the nature of the interactions within a complex system when it is subjected to cumulative stresses, crises and accidents. The objective is to identify, test and validate integrated emergency management procedures in the event of accidents, crises or major incidents occurring during the loading and unloading of goods and hazardous substances. To test the applicability of the framework, we developed a prototypal application identifying as a target complex system an Italian port area. An interactive simulation model was ad-hoc designed and developed, which makes it possible to reproduce the evolution of the crisis and its impact on structures, systems, people and goods by considering both the physical aspects and the domino effect in a multiple/sequential accidental scenario simulation. Additionally, it is possible testing the effectiveness of new technological and infrastructural solutions to reduce vulnerability, mitigate damage and prevent possible escalation of the event. Relevant accident scenarios were firstly thoroughly selected and subsequently integrated into a digital twin of the port. The interactivity allows a dynamic simulation of the possible actions of the different elements and active subsystems considered as a complex system, exploring their interactions in the face of crises and disasters, including the determining role of human factor.