In the process of long-term water flooding in the Gaoqian Southern Area with an average porosity of 30% and an average permeability of 1333.5×10−3 μm2, the fluid-solid interaction among oil, water, and rock has a great influence on the pore structure. It has resulted in changes in reservoir parameters with the extension of time. This paper used electron microscopy scanning, mercury injection, X-ray diffraction, physical properties, and oil-water relative permeability curves to study the variation of clay mineral content, pore throat structure, porosity, permeability, and relative permeability curves of high-permeability sandstone after high-pressure water flooding. The results showed that clay minerals such as montmorillonite and kaolinite were dissolved, hydrated, and migrated after long-term water flooding, which resulted in the decrease of clay mineral content in fine sandstone and medium sandstone, the increase of pore throat radius, and the decrease of displacement pressure, median pressure, and separation coefficient. The saturation of the isotonic point of the oil-water relative permeability curve was obviously shifted to the right, the hydrophilicity was significantly enhanced, and the porosity and permeability were effectively improved, but there was a blockage of the throat less than 2 μm in the fine sandstone. In addition, this paper established the equations of water injection, permeability, irreducible water saturation, residual oil saturation, and oil-water relative permeability curve coefficient and establishes the initial permeability model with the well data before water flooding. The logging interpretation results of development wells in the process of water flooding as verification data were used, and the relative error of permeability far lower than the general requirement of permeability error within an order of magnitude was less than 30%, which verified the rationality of the method.