The harsh environmental conditions bring strong nonlinearities to the hydrodynamic performances of the offshore floating platforms, which challenge the reliable prediction of the platform coupled with the mooring system. The present study investigates a typical semi-submersible under both the operational and the survival conditions through numerical and experimental methods. The motion responses, the mooring line tensions, and the wave loads on the longitudinal mid-section are investigated by both the fully non-linearly coupled numerical simulation and the physical experiment. Particularly, in the physical model test, the wave loads distributed on the semi-submersible’s mid-section were measured by dividing the model into two parts, namely the port and the starboard parts, which were rigidly connected by three six-component force transducers. It is concluded that both the numerical and physical model can have good prediction of the semi-submersible’s global responses. In addition, an improved numerical approach is proposed for the estimation of the mooring-induced damping, and is validated by both the experimental and the published results. The characteristics of the mooring-induced damping are further summarized in various sea states, including the operational and the survival environments. In order to obtain the better prediction of the system response in deep water, the mooring-induced damping of the truncated mooring lines applied in the physical experiment are compensated by comparing with those in full length. Furthermore, the upstream taut and the downstream slack mooring lines are classified and investigated to obtain the different mooring line damping performances in the comparative study.