The Pearl River Estuary (PRE) is one of the largest estuarine systems in China, which is subject to severe eutrophication, harmful algal blooms, and seasonal hypoxia driven by excessive nutrient and carbon inputs from the Pearl River basin. Over recent decades, intensive anthropogenic activities have substantially altered the nutrient and carbon cycles within the basin, yet the mechanisms by which these changes propagate to estuarine biogeochemistry and ecosystem functioning remain poorly understood. This study employs a coupled modeling framework combining the Finite Volume Community Ocean Model (FVCOM) with the Framework for Aquatic Biogeochemical Models (FABM) and the European Regional Seas Ecosystem Model (ERSEM) to simulate phytoplankton dynamics, primary productivity, and the cycling of nitrogen (N), phosphorus (P), and carbon (C) in the PRE from 2000 to 2024. Riverine nutrient and carbon fluxes derived from the HEIFLOW watershed model serve as boundary inputs for the ocean simulation. Basin-scale analyses reveal contrasting long-term trends: N inputs have increased primarily due to rising fertilizer application, while P inputs have declined as a result of afforestation and improved wastewater treatment. Concurrently, particulate organic carbon (POC) fluxes entering the PRE have decreased owing to increased dam construction, with a rising proportion of autochthonous carbon. Model results demonstrate that these shifting riverine loads have altered N-P ratios, restructured phytoplankton productivity patterns, and modified the nutrient cycling regime of the estuarine coastal system. These findings highlight the cascading effects of basin-scale anthropogenic drivers on estuarine ecology, with implications for seasonal hypoxia and long-term ecosystem health. The coupled watershed-estuary framework provides a comprehensive tool for understanding and managing estuarine ecosystems under sustained human influence.