In this research, experimental and mathematical modeling were carried out to estimate the permeability of tight sandstones. The pore structure parameters such as the number of pores, pore cross-sectional area, and pore radius were obtained by microcomputed tomography (micro-CT) scanning and image processing. A mathematical model was developed to predict the permeability of tight sandstones using the pore structure parameters. In the model, hydraulic radius was used to estimate the pore hydraulic conductance, where the pore diameter variation in a sinusoidal manner was observed. The stereological correction factor was used to characterize the arbitrary angle between the pore axis and the cross-sectional area. The tortuosity model was applied to characterize the behavior of non-Darcy flow inside the tight formations. Finally, the permeability prediction model was developed based on the effective medium theory. The proposed model was validated by 21 tight sandstone samples, with the relative errors within ±20%. In addition, due to the presence of small pores in tight sandstone with little contribution to overall permeability, the permeability shows inversely proportional behavior against the number of small pores.