In order to address the critical airworthiness issue concerning emergency egress safety during flight tests of large civil transport aircraft, a refined numerical simulation study based on computational fluid dynamics (CFD) was conducted. A coupled simulation method integrating the full aircraft aerodynamic flow field and crew multibody dynamics was constructed. The entire process of emergency egress from the side/rear cabin door by the flight test crew was systematically simulated using the dynamic overset mesh technology and a six-degree-of-freedom (6DOF) rigid body motion model. The coupling influence mechanisms of multiple factors, including flight speed, egress velocity, flap configuration, airflow angle, and propeller slipstream effects, on the egress trajectory and collision risk were thoroughly analyzed. The results indicate that egress velocity is the most sensitive parameter affecting safety and is positively correlated with the flight speed. For a certain large amphibious aircraft, an initial crew egress velocity of no less than 2.0 m/s can ensure safe egress within the corresponding flight envelope without unacceptable collision risks. The analysis methodology established, the parameter laws obtained, and the safety boundaries identified can provide support for the emergency egress scheme design, flight test risk assessment, and airworthiness compliance verification of similar aircraft.