The effect of dendritic structure and secondary phases on the fatigue crack propagation mechanism of ERNiCrMo-3 weld metal was investigated in the present study. Element segregation in the weld metal caused severe lattice distortion in the interdendritic region, which led to the instability of crack propagation rates, resulting in considerable differences in mechanical properties between the dendrite core and interdendritic region. The limited plastic deformation capability of the interdendritic region caused the contraction of the local plastic deformation zone at the crack tip, which increased stress concentration and accelerated crack propagation. Meanwhile, element segregation promoted the precipitation of a large number of Laves pahse in the interdendritic region. The interaction between dislocations and Laves phase was enhanced as the stress increased, which generated micro-voids and provided fast channels for fatigue crack propagation. Post-weld heat treatment weakened the non-uniformity of the microstructure and the fatigue crack showed a stable propagation trend. Moreover, the dissolution of Laves phase and the precipitation of γ” enhanced the fatigue property of the weld metal.