Abstract: In recent years, under global climate change, the frequent occurrence of extreme weather and climate events has posed severe threats to the safe operation of major projects in the Yangtze Estuary. As China’s largest estuary, the Yangtze Estuary serves multiple functions, including shipping, freshwater supply, and land development. The stability of its river regime is thus vital for regional economic growth and ecological security. However, due to the sharp reduction in sediment input from the Yangtze River basin and frequent fluctuations in marine hydrodynamic conditions, the river regime has undergone significant adjustments. The evolution of bars and channels has become increasingly complex and uncertain, while overall stability has declined. Against this backdrop, systematically analyzing safety risks and developing prevention strategies for major projects is of great theoretical and practical significance. Based on a comprehensive review of water–sediment dynamics and bar–channel evolution mechanisms over the past two decades, this study finds that since the impoundment and operation of the Three Gorges Reservoir, the sediment load discharged into the estuary has drastically decreased. The average annual sediment load has fallen by more than 70% compared with the 1950s–1980s, directly leading to continuous scouring of deep channels and frequent adjustments of shallow bar morphology. Coupled with the frequent occurrence of extreme events such as floods, typhoons, and saltwater intrusions in recent years, the regional engineering system now faces multiple risks. These phenomena show that the safety of single projects can no longer be ensured in isolation, highlighting the urgent need to establish a systematic risk assessment and prevention framework from the perspective of engineering clusters. To address these challenges, three major risk assessment systems are proposed for the Yangtze Estuary: navigation risks for deepwater channels, water supply security risks for water sources, and safety risks for enclosure projects. The assessment applied the analytic hierarchy process and established a multi-level, multi-indicator framework. Results indicate that the deepwater channel is at a medium risk level, with abnormal weather and rapid siltation as the most significant factors; the Chenhang water source faces the highest risks, mainly linked to operational management and saltwater intrusion; and some typical enclosure projects are expected to shift from low to higher risk levels over the next 30 years under ongoing water–sediment changes, with the Qingcaosha western dike showing particularly high potential risks. This study further proposes integrated engineering and non-engineering prevention strategies. For the deepwater channel, measures include suspended sediment monitoring, river regime evolution analysis, and predictive modeling using big data and artificial intelligence to improve dredging management. For water sources, combined strategies are recommended, such as strengthening operational management, mitigating saltwater intrusion, preventing eutrophication, and responding to sudden water quality incidents. For enclosure projects, strategies include enhancing bathymetric monitoring, implementing river regime regulation, improving embankment maintenance, and increasing disaster resistance, together with targeted reinforcement and risk mitigation measures. In addition, through numerical modeling and comparative analysis, a comprehensive river regime regulation scheme covering critical reaches such as Baimiao Shoal, the lower section of the South Channel, the South and North Passages, the South and North Channels, and the North Branch was developed, aiming to optimize the overall layout of engineering clusters and reduce systemic risks. The results indicate that after implementing the river regulation scheme, the comprehensive risk index for major projects in the Yangtze Estuary decreased overall. Navigation risks in the deepwater channel became more controllable, water supply security improved significantly, and enclosure projects generally remained at low risk levels. These findings not only verify the scientific soundness and feasibility of the proposed risk assessment framework and prevention strategies but also provide solid technical support and management guidance for ensuring the safe operation of major projects in the Yangtze Estuary under changing water–sediment conditions.