Abstract: As one of the sub-centers of Guangzhou, Nansha District has long been a critical area for managing flood and storm surge risks due to its distinctive location at the Pearl River estuary and its exposure to both fluvial flooding and coastal surges. With the growing impacts of climate change and intensified human activities, the district now faces increasing threats from sea level rise, land subsidence, and extreme weather events—factors that collectively heighten flood risk and threaten regional development. Enhancing Nansha’s flood and storm surge resilience is therefore essential to safeguarding local populations and infrastructure. This study establishes a two-dimensional hydrodynamic model using TELEMAC, focusing on the Pearl River Delta’s river network and Nansha’s low-lying zones. Based on this model, scenario simulations were conducted to quantitatively evaluate the inundation characteristics and defense performance under different conditions, including current design standards and projected future scenarios that account for sea level rise, land subsidence, and extreme storm surge events exceeding standard thresholds. The simulation results show that, under current standard conditions, the inundation area in Nansha District reaches about 59 square kilometers in the storm surge-dominated scenario and 48 square kilometers in the upstream flood-dominated scenario. This highlights the dual influence of coastal and riverine flooding on inundation risks, underscoring the need for integrated defense strategies. To address these challenges, two flood protection schemes were assessed: a standalone levee system and a combined sluice-levee system. Under current standard conditions, the levee-only scheme effectively prevents inundation across the study area, demonstrating its adequacy for the existing hydrodynamic environment. However, in future scenarios that include sea level rise and land subsidence—anticipated to intensify over the next 30 years—the effectiveness of the levee-only scheme diminishes. Specifically, in the storm surge-dominated future scenario, the inundated area expands to 22 square kilometers, indicating that levees alone may no longer provide adequate protection. In contrast, the combined sluice-levee system, which incorporates gated hydraulic structures alongside embankments, performs better, especially under storm surge conditions. While its impact is limited in upstream flood-dominated scenarios, it notably improves water level regulation and flow patterns during storm surges. This results in enhanced protective performance, particularly in the northwestern polder areas of Nansha, where storm surge risks are most acute. Quantitative analyses further highlight the advantages of the combined scheme: compared to the pure levee approach, the sluice-levee configuration reduces inundation extent by up to 50% under future scenarios involving sea level rise and land subsidence. Even under extreme storm surges exceeding current design thresholds, the reduction in inundated area ranges from 12% to 18%, demonstrating the added value of flexible and adaptive infrastructure in addressing uncertain future conditions. Overall, this research underscores the importance of incorporating dynamic environmental changes into flood risk management. Through the application of advanced numerical modeling and scenario-based evaluation, it provides scientific support for selecting optimal flood defense strategies in estuarine urban settings like Nansha. The results serve not only as a reference for local decision-makers and planners but also offer broader insights for other coastal cities confronting similar flood and storm surge adaptation challenges.