Aiming at the problem that the purposive maneuver of the guided projectile is difficult to be realized during its short flight time, a method based on large acceleration change using double-vector observations for the in-flight alignment was proposed. First, according to the navigation velocity rate equation, double-vector observations were derived, and the Request algorithm was introduced for the initial attitude estimation. Then, error analysis was discussed, which puts forward a large acceleration change for the in-flight alignment. Simulation experiment analyzed and discussed the effectiveness of the proposed large acceleration change for the in-flight alignment. The simulation result indicated that the in-flight alignment can be achieved quickly, and the heading misalignment error is about 0.3°, the pitch and rolling misalignment errors are less than 0.2°.