Safety is essential for sustainable aviation fuels (SAFs). However, evaluating SAFs’ impacts on aero-engine safety is challenging because it involves multiple space scales and the strongly coupled relationships of aero-engine components. Aiming at addressing this problem, a model-based approach is proposed to establish the relationship between the fuel-level physical properties and engine-level safety parameters. Firstly, a unified modeling criterion is proposed to consider the interrelations of aero-engine components. Under this criterion, aero-engine secondary air system (SAS) components are included in SAF safety assessment, since they have non-neglectable influences on aero-engine safety. Secondly, this paper proposes a surrogate-based iteration strategy to embed the combustor’s high-dimensional computational fluid dynamics (CFD) model into the aero-engine flow network model. Then, the proposed model-based safety assessment approach is applied to a Fischer–Tropsch hydro-processed synthesized paraffinic kerosine (F-T SPK) safety assessment case. The effects of fuel flow and blending ratio are considered. The results indicate the necessity to evaluate SAFs’ safety at the aero-engine level and consider the influences of SAS components. The proposed model-based approach may provide a preliminary screening before SAFs’ certification tests. This convenience may be beneficial for reducing the cost and accelerating SAFs’ application.