Abstract: The macro-tidal estuary with a mountain stream is a typical estuary on China′s southeast coast, characterized by intense dynamic forces, active sediment movements, and a robust response to human activities. It demands further investigation of its evolution mechanism under both natural conditions and anthropogenic stresses. This paper takes the Jiangxinyu reach of the Oujiang River estuary as a case example to explore the river′s evolution under the influence of human activities, including effects of longitudinal dam construction, sand mining, and shoreline adjustment since the 1970s. Measured data analysis and a two-dimensional flow and sediment mathematical model were used. The results confirm that anthropogenic stresses have altered the natural periodic alternation of the river′s main and side branches. Moreover, the undercutting of the riverbed caused by sand mining from the beginning of this century has increased tidal range by 0.5 m and tidal prism by 47%, while weakening the discharge asymmetry and sediment transport asymmetry indices by 0.08—0.30 and 0.28—0.54, respectively. The undercutting of the riverbed has also weakened the ebb and flood asymmetry. These conditions have subsequently helped slow down the shrinkage of the side branch. The evolution mechanism is dominated by both natural and human activities. Overall, the research findings may be a reference for river evolution and protection under the influence of human activities.