The effect of dendritic structure and secondary phases on the fatigue crack propagation mechanism of ERNiCrMo-3 weld metal was investigated. Element segregation in the weld metal induced severe lattice distortion in the interdendritic region, creating substantial variations in mechanical properties between the dendrite core and interdendritic region. This disparity resulted in an unstable crack propagation rate. The limited plastic deformation capacity of the interdendritic region caused a contraction in the local plastic deformation zone at the crack tip, increasing stress concentration and accelerating crack propagation. The fatigue crack in the interdendritic regions exhibited a rate of approximately 2.6 μm/cycle, surpassing the 1.5 μm/cycle observed in the dendrite cores. Meanwhile, element segregation promoted the precipitation of numerous Laves phases in the interdendritic regions. With increasing stress, micro-voids formed by broken Laves phases served as rapid channels for crack propagation. Post-weld heat treatment weakened the non-uniformity of the microstructure. The fatigue crack propagated at a rate of about 1.2 μm/cycle. Furthermore, the dissolution of Laves phases and the precipitation of γ″ enhanced the fatigue performance of the weld metal. Under equivalent stress levels, the fatigue life of post-weld heat-treated weld metal increased by approximately 1.2 times compared to that of as-welded metal.