Taking clay rock as the research object, scanning electron microscope tests have been carried out under the conditions of resaturation and in-situ stress, and three-dimensional porosity was used to quantitatively analyze the structural changes. The microstructure characteristics and macro and micro mechanism of self-sealing were studied. The results show that: Under the condition of no external force, the self-sealing is mainly characterized by hydration-swelling and anisotropy. The vertical bedding and parallel bedding are mainly characterized by granular unit disintegration and lamellar structure spalling, respectively. Clay particles are constantly swelling, spalling, caving and stacking to fill the void in a loose state. The degree of self-sealing is positively correlated with the resaturation time. Under the action of stress and heating, the self-sealing is dominated by compression and compaction, the particles are fine, and the structure changes from loose to agglomeration state. The mechanism of self-sealing is related to hydrochemistry and volume strain. The content of expansive clay minerals and long resaturation time are conducive to the self-sealing of fractures. Stress, heating and long-term creep lead to volume compression, structure becomes dense and promotes the self-sealing of fractures, whereas volume expansion inhibits it. The research results can provide surpport for geological site selection and safety assessment of clay rock high-level radioactive waste.