Abstract: Lost circulation of drilling fluid is an international engineering problem during drilling. Aiming at the problems of the first-time lost circulation control success rate and poor adaptability of traditional lost circulation materials, a new self-healing lost circulation material based on dynamic disulfide bonds was prepared and named CKSH. In this paper, the particle size of self-healing lost circulation material was from 0.1 to 5 mm. The structure was analyzed by modern characterization means, and the drilling fluid compatibility, self-healing performance were evaluated. The self-healing and bridging-filling-sealing mechanism of CKSH were revealed. The results showed that the healing rate of CKSH could reach 100% after 12 h over 70 °C. It showed good compatibility with drilling fluid, with no effect on rheology or filtration loss. It could be stably suspended in drilling fluid, and the temperature resistance reached 140 °C. Healing by self-healing lost circulation materials of different particle size, the pressure bearing capacity of plugging zone were over 12 MPa for fracture opening of 1–5 mm. It could play a synergistic role with traditional lost circulation materials by chemical bonding, and the repeated loss caused by physical plugging was avoided. The research results of this paper can improve the bridging plugging bearing pressure strength and the first-time lost circulation control success rate, which is of great significance for improving drilling efficiency and reducing non-productive time.