Conceptual frameworks are valuable resources that can be used to guide the planning, evaluation, and development of healthcare services. However, there are currently no comprehensive frameworks focused on organ donation and transplantation that identify the critical factors underlying a successful national program. To address this knowledge gap, we developed a conceptual framework that takes into account all major domains of influence, including political and societal aspects as well as clinical implementation. The framework was initially constructed based on a targeted review of the relevant medical literature. Feedback provided by a panel of international experts was incorporated into the framework via an iterative process. The final framework features 16 essential domains that are critical for initiating and maintaining a successful program and improving the health of patients with organ failure. Of particular note, these domains are subject to three overarching health system principles: responsiveness, efficiency, and equity. This framework represents a first attempt to develop a whole-system view of the various factors that contribute to the success of a national program. These findings provide a useful tool that can be adapted to any jurisdiction and used to plan, evaluate, and improve organ donation and transplantation programs.