Compound flooding (CF) is driven by the river-ocean interactions in the coastal zone, particularly when coastal backwater propagates upstream and interacts with river discharge. The modeling of CF is limited in Earth System Models (ESMs) due to insufficient mesh resolution and loosely coupled river-ocean components. In this study, we present a novel multi-scale coupling framework within the Energy Exascale Earth System Model (E3SM). The new framework integrates global atmosphere, land and interactively coupled river and ocean models, with the land, river, and ocean models configured on variable-resolution meshes with refinements near the coastline. To evaluate this framework, we performed ensemble simulations of a CF event (Hurricane Irene) in a Mid-Atlantic estuary. The results demonstrate that with the novel framework, E3SM can reproduce river discharge and sea surface height reasonably well. The interactive river-ocean coupling improves the representation of coastal backwater effects at the terrestrial-aquatic interface, thus providing a valuable modeling tool for better understanding the river-estuary-ocean dynamics in extreme events under climate change. Notably, our results show that the most significant CF impacts occur when the highest storm surge generated by a tropical cyclone co-occurs with a moderate river discharge. This study highlights state-of-the-art modeling techniques developed within the global E3SM framework for simulating multi-scale coastal processes.