The Two-Stage-to-Orbit (TSTO) spacecraft can generate complex, unsteady aerodynamic interference during high-speed inter-stage separation, thereby increasing the risk of separation failure. This study explores the complex aerodynamic disturbance characteristics and separation safety across various strategies. A multi-body separation simulation flow, which supports multiple dynamic grid methods, was developed, using a wide-velocity wave rider and a reusable aerospace composite vehicle as the research subjects. Overset grid technology was employed to address the issue of large grid movement between the two stages, while deform mesh technology was utilized to manage the small changes in grid following rudder surface deflection. The flow control equation and the six-degree-of-freedom rigid body dynamics equations were solved by coupling. Dynamic numerical simulations of the separation process under different strategies, such as longitudinal/transverse and rudder plane with/without deflection, were conducted under high-speed flow conditions. The results indicated that the attitude change of the orbital stage during longitudinal separation is more stable compared to transverse separation. The deflection of the flat tail stabilizer of the orbital stage enhanced flight stability during separation, thereby improving the safety of inter-stage separation.