Due to the tall and large superstructures of cruise ships, the wind-induced vibration of frame structure on open decks cannot be neglected. This study investigated the wind-induced vibration of a typical frame structure on a cruise ship by using wind tunnel tests and numerical simulations. Wind tunnel tests were conducted to explore the simulation methods of the fluid–structure interaction (FSI). CFD simulations were performed to obtain the wind field data of the entire ship, which was utilized as an input for the open deck through the subdomain method. Subsequently, wind-induced vibration simulations of the guide rail frame structure on the open deck was carried out under various wind conditions. The results revealed that employing the turbulence model SST k-ω had a good agreement with the experimental data. The entire ship’s CFD results have a significant impact on the subdomain’s wind-induced vibration results. The vibration frequency of the guide rail frame structure was mainly concentrated between 0.8–10.1 Hz. The most unfavorable conditions appear at the wind attack angles of 0° and 120°. This study can provide some instructive insights for the prediction of wind-induced vibration and control of typical structures on the open decks of large cruise ships.