This study investigates the sensitivity of the Calcasieu Lake estuarine region to channel deepening in southwest Louisiana in the USA. We test the hypothesis that the depth increase in a navigational channel in an estuarine region results in the amplification of the inland penetration of storm surge, thereby increasing the flood vulnerability of the region. We run numerical experiments using the Delft3D modeling suite (validated with observational data) with different historic channel depth scenarios. Model results show that channel deepening facilitates increased water movement into the lake–estuary system during a storm surge event. The inland peak water level increases by 37% in the presence of the deepest channel. Moreover, the peak volumetric flow rate increases by 291.6% along the navigational channel. Furthermore, the tidal prism and the volume of surge prism passing through the channel inlet increase by 487% and 153.3%, respectively. In our study, the presence of the deepest channel results in extra 56.72 km2 of flooded area (approximately 12% increase) which is an indication that channel deepening over the years has rendered the region more vulnerable to hurricane-induced flooding. The study also analyzes the impact of channel deepening on storm surge in estuaries under different future sea-level rise (SLR) scenarios. Simulations suggest that even the most conservative scenario of SLR will cause an approximately 51% increase in flooded area in the presence of the deepest ship channel, thereby suggesting that rising sea level will cause increased surge penetration and increased flood risk.