The availability of detailed environmental hindcast data opens the door for virtual structural health monitoring; however, the impact of hindcast wave data selection on the results of such an approach have not been explored. While studies on the differences between wave models have been conducted in the past, extensions of these comparisons to resultant vessel response predictions and fatigue damage estimates are limited. At three separate geographical locations, this work compared hindcast wave data from NOAA’s WAVEWATCH III (NWW3) Multigrid Production Hindcast, the EU’s CMEMS Global Ocean Waves Analysis and Forecasting Product, and National Data Buoy Center buoys. In addition to comparisons of wave parameters at each location, the resultant heave, pitch, and vertical bending moment responses and fatigue damage of a destroyer-sized naval combatant, the DTMB 5415, were compared. The novelty of this work lies in its large scope, which calculated responses every 3 h for all of 2017 in 32 speed and heading combinations for each location and wave data source. The results show that differences between wave data sources propagated to the vessel response predictions. These differences were then amplified in the calculation of fatigue damage causing significant discrepancies between data sources after just one year.