This study aimed to elucidate the damage mechanism of prestressed sandstone under uniaxial compression through the distribution characteristics of meso-structures. Four prestress levels, i.e., 0MPa, 15MPa, 30MPa, and 40MPa were selected. Nuclear Magnetic Resonance and Scanning Electron Microscope techniques were employed to observe the distribution characteristics of meso-structure within rocks and to further its damage mechanism. The results show that, compare with untreated specimens (0MPa), damaged specimens by 15MPa show a more porous meso-structure due to pores/cracks propagation which occurs between skeleton minerals and filler materials. Furthermore, specimens treated by 30MPa and 40MPa show low failure strength because micro-pores/cracks initiation inside skeleton minerals causes high deterioration. By meso-mechanics analysis, particle rotation leads to pores/cracks propagation and slightly modifies the meso-structure under low-prestress conditions. With the increase of the prestress, the transgranular cracks initiation and propagation will transform the skeleton structure of rocks, leading to significant rock deterioration.