The microstructure evolution and deformation mechanism of a DZ125 superalloy during high-temperature creep were studied by means of microstructure observation and creep-property tests. The results show that at the initial stage of high-temperature creep, two sets of dislocations with different Burgers vectors move and meet in γ matrix channels, and react to form a quadrilateral dislocation network. And γ′ phases with raft-like microstructure are generated after the formation of dislocation networks. As creep progresses, the quadrilateral dislocation network is gradually transformed into hexagonal and quadrilateral dislocation networks. During steady stage of creep, the superalloy undergoes deformation with the mechanism that a great number of dislocations slip and climb in the matrix across the raft-like γ′ phases. At the later stage of creep, the raft-like γ′ phases are sheared by dislocations at the breakage of dislocation networks, and then alternate slip occurs, which distorts and breaks the raft-like γ′/γ phases, resulting in the accumulation of micropores at the raft-like γ′/γ interfaces and the formation of microcracks. As creep continues, the microcracks continue to expand until creep fracture occurs, which is the damage and fracture mechanism of the alloy at the later stage of creep at high temperature.