In order to study the salinity diffusion characteristics of the waters near the estuary under the changing runoff of the Yellow River into the sea and to protect better the diversity of biological resources in the estuary, the offshore hydrodynamic model FVCOM is used to analyze the influence of runoff variations on salinity of the estuary waters based on the long series of runoff data from the Lijin Hydrological Station. The results show that there is a clockwise circulation system between the Yellow River estuary and the Laizhou Bay. Under the function of residual flow and the influence of tidal current directions, the diluted water of the Yellow River diffuses in long term toward the Laizhou Bay. In wet seasons the Yellow River diluted water affects almost the whole Laizhou Bay. The 27 salinity front can reach to the central part of the Laizhou Bay and the surface envelope area of the 27 salinity isohaline can be 2 665.61 km², accounting for about a quarter of the size of the Laizhou Bay. In dry seasons, however, low-salinity water only tends to diffuse southward. The water with salinity lower than 27 is mainly distributed in the area near the Yellow River mouth and the surface envelope area of the 27 salinity isohaline can only be 199.65 km². In May, the range, distance and direction of the 27-salinity line diffusion vary distinctly with the increase in the volume of runoff into the sea. In the situations where there are urgent protection needs for offshore biological resources, appropriately reducing the water supply of other water users to increase the ecological runoff volume into the sea can effectively improve the salinity situation of the waters of the Yellow River Estuary and create good conditions for the growth and reproduction of biological resources.