Introduction: A full-scale simulation exercise is a comprehensive drill designed to replicate a real-world emergency scenario, thereby identifying the strengths and weaknesses in current practices. The overarching goal is to enhance healthcare system resilience through improved protocols, as highlighted in this systematic review tailored for researchers. The study aims specifically to assess the impact of full-scale simulations on enhancing hospital disaster plans. Methodology: Following PRISMA guidelines, this systematic review investigates the impact of full-scale simulation exercises on hospital disaster preparedness. The focus was on hospital staff involved in disaster and emergency preparedness training. The primary intervention was the execution of full-scale simulation exercises, and our research included various study designs, including randomised controlled trials and observational study designs. A comprehensive electronic database search was conducted, spanning PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials, from inception until October 9, 2023. The risk of bias was assessed using NIH tools. Results: The literature search yielded 2398 results, with 28 publications finally included in the systematic review. Summarising a broad range of disaster preparedness simulation exercises with a specific focus on full-scale simulation (FSS), the studies consistently demonstrated a positive impact on participants' skills, as well as identifying safety issues in hospital settings. Moreover, they revealed that simulations effectively addressed crucial areas for improvement in disaster response, including communication breakdowns, equipment deficiencies, and flaws in emergency plans. The studies utilised a multidimensional approach to evaluation metrics, encompassing non-technical skills, communication, teamwork, decision-making, and operational readiness. The exercises varied in duration from 30 minutes to multi-day simulations, covering a diverse range of disaster scenarios, such as mass casualties, viral epidemics, large aviation accidents, and terrorist attacks. Conclusion: Full-scale simulation exercises are a preparatory learning tool to test facility and staff readiness for complex emergencies. This systematic review focused on the different exercise scenarios used to address critical aspects of disaster response such as communication breakdowns, equipment deficiencies, and flaws in emergency plans. The scenarios and their duration were varied, and involved a multidimensional approach to evaluation. Such exercises enhance critical thinking and problem-solving skills, increase familiarity with potential emergencies, and build confidence in making judgments in real-world situations. In our opinion, there is a need for further programs that align simulation exercises with community resources for better preparedness in the face of public health disasters.