Nowadays, with the escalating tensions in maritime dispute and the development of marine economy, there has been renewed interest in seaplanes for their special capacity of taking off and landing on water. Prediction of take-off performance, involving aerodynamic analysis and hydrodynamic analysis, is a main challenge in seaplane design, while the prediction methods have been little improved since the 1960s. This paper aims to investigate the attitude and resistance characteristics of a seaplane at different speeds during the take-off by numerically modeling the air-water flow field using RANS equations with VOF method. The trim and heave motion of seaplane in response to aerodynamic forces, hydrodynamic forces, hydrostatic forces, and propeller thrust was realized by solving rigid body dynamics equations and adopting dynamic overset mesh technique. The variations in heave, trim angle, and resistance characteristics during the takeoff were investigated, and their inherent relationships with the aerodynamic, hydrodynamic, and hydrostatic performance were revealed. Particular investigation on the hydrodynamic resistance indicates that the stagnation line located at the convex bow would contribute a considerable increase of pressure resistance at the first hump, and the trim angel of a seaplane should be operated in an optimum trim range, typical between 4–6 deg, to minimize the hydrodynamic resistance at the second hump. Additionally, the dynamic motion convergence study proves that the utilization of damping terms was an effective way to accelerate the convergence of the dynamic motion ending with a quasi-static state.