This study aimed to investigate the in vivo dissolution of tricalcium silicate (Ca3SiO5, C3S) bone cement in the rabbit femoral defect. Results indicated that C3S paste directly integrated with the bone tissue without the protection of the bone‐like apatite. Calcium silicate hydrate gel (C–S–H gel) and Ca(OH)2 were the main components of C3S paste. The dissolution model of C3S paste was a mass loss rather than a decrease in volume. The initial dissolution of C3S paste (0 ~ 6 weeks) was greatly attributed to the release of Ca(OH)2, and the later dissolution (>6 weeks) was attributed to the decalcification of C‐S‐H gel. Although the mass of C3S paste could decrease by more than 19 wt % after 6 weeks of implantation, the created pores (<1 μm) were not large enough for the bone tissue to migrate into C3S paste. The loss of Ca ions also resulted in the transformation of SiO4 tetrahedrons from Q1 and Q2 to Q0, Q3, and Q4 in C‐S‐H gel. Because only isolated SiO4 tetrahedrons (Q0) and Ca ions could be absorbed by the bone tissue, C3S paste gradually transformed into a silica‐rich gel. The fundamental reason for no decrease in volume of C3S paste was that the SiO4 tetrahedron network still maintained the frame structure of C3S paste during the implantation.