The effect of the scarcely reported F phase on hydrogen-assisted cracking in nickel-based Alloy 725 was thoroughly studied by combining tensile tests, advanced characterization, and density functional theory (DFT) calculations. The results show grain boundary precipitate F phase promotes intergranular fracture in a hydrogen environment. DFT calculations further indicates hydrogen atoms lower the binding strength of the F phase and Ni matrix interfaces. More importantly, our study showed for the first time that the addition of approximately 0.01 wt.% boron can effectively suppress F phase precipitation, thereby elevating the hydrogen resistance of Alloy 725.