The effect of γ/γ′ phase lattice misfit on hydrogen embrittlement (HE) behavior was fundamentally investigated by utilizing a Ni-based single crystal CMSX-4 superalloy with a simple microstructure that can exclude the H-trapping effects of grain boundary, c-vacancy, and misfit dislocation. Increasing isothermal aging time increased γ′ precipitate size while maintaining its volume fraction and a fully coherent interface. The magnitude of negative lattice misfit between the γ and γ′ phases increased from −0.08 to −0.22% according to γ′ precipitate coarsening, resulting in a well-developed tensile-strain field within the γ′ precipitate. The increased tensile-strain field enhanced activation energy for H-desorption in the γ′ precipitate from 31.9 to 35.1 kJ/mol. Therefore, H is preferentially distributed along the γ/γ′ interface within the γ′ precipitate even before deformation. H basically promotes the slip planarity through the H-enhanced localized plasticity (HELP) mechanism in Ni-based single crystal alloys, in which slip is the dominant deformation behavior. As the superalloy possesses a larger negative lattice misfit, H becomes trapped as diffusible-state at the tensile-strain field of the γ/γ′ interface, resulting in cuboidal brittle fracture along the {001} planes. In this process, the HELP mechanism facilitated H localization at the γ/γ′ interface. Thus, the HE behavior distinctly transitioned from HELP to an interaction between HELP and H-enhanced decohesion mechanisms (HEDE) with an increase in the magnitude of the lattice misfit. The HE behavior was investigated by correlating microstructural characterization, H-trapping behavior, and crystallographic fracture mechanism analysis.