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Coastal zone compound flooding (CF) can be caused by the interactive fluvial and oceanic processes, particularly when coastal backwater propagates upstream and interacts with high river discharge. The modeling of CF is limited in existing Earth System Models (ESMs) due to coarse mesh resolutions and one‐way coupled river‐ocean components. In this study, we present a novel multi‐scale coupling framework within the Energy Exascale Earth System Model (E3SM), integrating global atmosphere and land with interactively coupled river and ocean models using different meshes with refined resolutions near the coastline. To evaluate this framework, we conducted ensemble simulations of a CF event (Hurricane Irene in 2011) in a Mid‐Atlantic estuary. The results demonstrate that the novel E3SM configuration can reasonably reproduce river discharge and sea surface height variations. The two‐way river‐ocean coupling improves the representation of coastal backwater effects at the terrestrial‐aquatic interface that are caused by the combined actions of tide and storm surge during the CF event, 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 meets with a moderate river discharge. This study highlights the state‐of‐the‐art advancements developed within E3SM for simulating multi‐scale coastal processes. Plain Language Summary: Compound flooding (CF) happens when rivers and oceans interact in the coastal zone. There are limitations in current models to accurately simulate these processes because of the insufficient resolutions in the computational meshes and lack of details on how rivers and oceans are connected. This study creates a comprehensive framework for the Energy Exascale Earth System Model (E3SM) and demonstrates its ability to simulate a specific compound flooding event in a Mid‐Atlantic estuary. Our framework combines models of the atmosphere, land, river, and ocean, each with its own level of detail near the coastline to account for their different physical processes. Our results show that the E3SM framework can reproduce the river discharge and sea level variations reasonably well. By simulating the interaction between river and ocean, we can better understand the effects of coastal water on river discharge forced by tides and storm surges during the CF event. Our simulation reveals that CF is most significant when a tropical cyclone produces the highest storm surge but moderate river discharge. This study demonstrates the capability of the E3SM model to accurately simulate the detailed coastal processes. Key Points: An Energy Exascale Earth System Model (E3SM) configuration is developed to integrate variable‐resolution meshes with component advancementsThe two‐way river‐ocean coupling scheme developed in E3SM significantly improves the representation of river‐ocean interactionsThe new coupled E3SM configuration provides insights into the nonlinear interactions between storm surge and river discharge during compound flooding [ABSTRACT FROM AUTHOR]