Hurricanes interact with the Gulf Stream in the South Atlantic Bight (SAB) through a wide variety of processes, which are crucial to understand for prediction of open-ocean and coastal hazards during storms. However, it remains unclear how waves are modified by large-scale ocean currents under storm conditions, when waves are aligned with the storm-driven circulation and tightly coupled to the overlying wind field. Hurricane Matthew (2016) impacted the US southeast coast, causing extensive coastal change due to large waves and elevated water levels. The hurricane traveled on the continental shelf parallel to the SAB coastline, with the right side of the hurricane directly over the Gulf Stream. Using the Coupled Ocean Atmosphere Wave Sediment Transport Modeling System, we investigate wave-current interaction between Hurricane Matthew and the Gulf Stream. The model simulates ocean currents and waves over a grid encompassing the US east coast, with varied coupling of the hydrodynamic and wave components to isolate the effect of the currents on the waves, and the effect of the Gulf Stream relative to storm-driven circulation. The Gulf Stream modifies the direction of the storm-driven currents beneath the right side of the hurricane. Waves transitioned from following currents that result in wave lengthening, through negative current gradients that result in wave steepening and dissipation. Wave-current interaction over the Gulf Stream modified maximum coastal total water levels, and changed incident wave directions at the coast by up to 20°, with strong implications for the morphodynamic response and stability of the coast to the hurricane.