Based on the measured runoff and tide level data of the long series from 1960 to 2019, Mann-Kendall test and Theil-Sen estimation were used to analyze the runoff variability of the Yangtze River Estuary and the trend of sea level change. In combination with MIKE21 hydrodynamic model and Monte Carlo method, a method for calculating the over standard rate of salinity was proposed, and the risk of saltwater intrusion into the Yangtze River inlet was assessed. The results show that the annual variance of runoff logarithms and the average sea level height show a significant downward and upward trend, respectively. It is estimated that the annual variances of runoff logarithms will decrease by 30% and 60% respectively by 2060 and 2100, and the average sea level height will increase by 0.2 m and 0.4 m respectively. The sea level rise increases the over standard rate of salinity at the Yangtze River Estuary, which is relatively obvious in the middle section of the estuary. With the decrease of runoff rheological anisotropy, the over standard rate of salinity along the Yangtze River Estuary rises and falls alternately. In 2060 and 2100, the over standard rate of the average salinity in the Yangtze River Estuary will increase from 46.9% to 52.2% and 54.9% respectively, in which the influence of sea level change on the saline intrusion in the Yangtze River Estuary is significantly greater than that of runoff variation.