River regime changes have a substantial impact on estuary hydrodynamics and the incidence of saltwater intrusion. Based on measured water depth data in the North Branch of the Yangtze River Estuary from 2007 and 2016, we analyzed the river regime changes of the North Branch across a 10-year timespan; in addition, we numerically simulated and analyzed the influence of the river regime change on hydrodynamics and saltwater intrusion. The water volume increased by 4.4% in the upstream section, decreased by 8.8% in the midstream, and decreased by 20.5% in the downstream of the North Branch from 2007 to 2016. Overall, the data reflects an overall net erosion in the upstream section and deposition in the midstream and downstream sections of the North Branch. In fact, a new sand body with deposition thickness of 4 ~ 6 m appeared in the bifurcation of the North Brach and South Branch. The numerical simulation results, moreover, show that the new sand body caused a 15.0% increase in saltwater intrusion, a change in net water diversion ratio from –2.8% to –3.2% in the upstream section of the North Branch during spring tide, and clear enhancement of saltwater intrusion; if the new sand body continues to deposit up to 0.85 m, the saltwater intrusion will not increase further. At the water intakes of the three reservoirs in the South Branch, the new sand body caused the average salinity during spring tide to increase by 0.14 at Dongfengxisha reservoir, 0.12 at Chenhang reservoir, and 0.11 at Qingcaosha reservoir; similarly, the average salinity during the subsequent middle tide increased by 0.15 at Dongfengxisha, 0.11 at Chenhang, and 0.09 at Qingcaosha. The deposition in the downstream section of the North Branch led to tidal prisms cross section at the port of Lianxin during flood tide and ebb tide to decrease by 15.2% and 16.4%, respectively, in spring tide, and decrease by 21.2% and 19.0%, respectively, in neap tide. As we move further upstream along the North Branch: the amount of rising and falling tides decreases and shows a relative downward trend, the high tide level drops, the low tide level rises, and the tidal range decreases during spring tide. Moreover, the tidal prisms in the midstream and downstream sections of the North Branch decreased, and the saltwater spillover from the North Branch into the South Branch weakened. The deposition in the downstream section of the North Branch caused the salinity decrease at the water intakes of the three reservoirs of the South Branch. On the whole, the saltwater spillover from the North Branch to the South Branch weakened significantly due to the river regime changes in the North Branch from 2007 to 2016; the salinity decreased by 2 ~ 3 in the upstream section of the North Branch and 1 ~ 2 in the downstream section of the North Branch; the salinity decreased at the water intakes of the three reservoirs of the South Branch; and the average salinity during spring tide and the subsequent middle tide decreased by 0.41 and 0.21, respectively, at Dongfengxisha reservoir, decreased by 0.34 and 0.18, respectively, at Chenhang reservoir, and decreased by 0.28 and 0.17, respectively, at Qingcaosha reservoir.