Old Cairo is a unique site in the world because of its historical, cultural, and religious values. Old Cairo, a UNESCO World Heritage site, represents a rich tapestry of history and culture. Its significance lies in its role as a center of Coptic and Islamic civilizations and its preservation of numerous historical monuments. Today, the conservation of cultural heritage demands a proactive approach that integrates a robust multidisciplinary strategy. This approach must consider the unique characteristics of the heritage itself and the extensive research and efforts devoted to various scientific fields and avenues. As a case study, the focus is on the Religions Complex, the target of the “Particular Relevance” bilateral Italy–Egypt “CoReng” project. The historic Religions Complex in Old Cairo, a UNESCO World Heritage site, faces significant seismic hazards, threatening its irreplaceable Coptic and Islamic heritage. This research contribution focuses on reviewing and assessing aspects of geological and seismic hazards. This assessment serves as a crucial foundation for future vulnerability analyses and the development of effective retrofitting strategies for the Complex’s historic structures. The current work identifies critical vulnerabilities related to sub-surface geology and geotechnical conditions, various deterioration driving forces, rising groundwater levels, and earthquake ground shaking of the complex site to mitigate these risks and ensure the long-term preservation of this invaluable cultural heritage. In addition, attention is given to missing/weak characterization aspects and the proposal of possible future solutions and research developments.