To reduce the environmental impact of aviation, aircraft manufacturers develop novel aircraft configurations and investigate advanced systems technologies. These new technologies are complex and characterized by electrical or hybrid-electric propulsion systems. Ensuring that these complex architectures are safe is paramount to enabling the certification and entry into service of new aircraft concepts. Emerging techniques in systems architecting, such as using model-based systems engineering (MBSE), help deal with such complexity. However, MBSE techniques are currently not integrated with the overall aircraft conceptual design, using automated multidisciplinary design analysis and optimization (MDAO) techniques. Current MDAO frameworks do not incorporate the various aspects of system safety assessment. The industry is increasingly interested in Model-Based Safety Assessment (MBSA) to improve the safety assessment process and give the safety engineer detailed insight into the failure characteristics of system components. This paper presents a comprehensive framework to introduce various aspects of safety assessment in conceptual design and MDAO, also considering downstream compatibility of the system architecting and safety assessment process. The presented methodology includes specific elements of the SAE ARP4761 safety assessment process and adapts them to the systems architecting process in conceptual design. The proposed framework also introduces a novel safety-based filtering approach for large system architecture design spaces. The framework’s effectiveness is illustrated with examples from applications in recent collaborative research projects with industry and academia. The work presented in this paper contributes to increasing maturity in conceptual design studies and enables more innovation by opening the design space while considering safety upfront.