The response of a coastal region to sea-level rise depends on the local physical features, which should therefore be evaluated locally to provide an accurate vulnerability assessment. In this study, we conducted comprehensive analyses of the potential impacts of sea-level rise on the Pearl River Estuary (PRE), China with the aid of a fully calibrated three-dimensional hydrodynamic model. We found that in general, the salinity, stratification and tidal range will increase as the sea-level rises. Clear spatial variations were apparent in the response of these parameters, with different patterns occurring in different seasons. The strongest salinity increase was mostly at the front of the PRE, where freshwater and saltwater meets. In Lingding Bay (LDB), the rate of increase in stratification in response to the sea-level rise was found to be higher during high-flow conditions than that during low-flow conditions. The increases of tidal range and tidal current were amplified in the upstream direction, with the largest increase occurring in the upper tributaries. The change of vertical transport process in the PRE is not prominent and only in the upper LDB the vertical transport time increased for approximately two days. The upstream transport process was strengthened during the typical wet season and weakened during the typical dry season. The downstream transport slowed in both wet and dry seasons as the sea level rose. For a sea-level rise of 1 m, the dry season residence time increased by 8.5 days, while the wet season residence time showed only minor changes. It was also found that the fluvial input remained in the PRE for a longer time after the sea level rose, which would increase the retention time of dissolved substances and thus effect biogeochemical processes.