The microstructure and grain-boundary misorientation of X80 high-strength pipeline steel are analyzed using the scanning electron microscope, the electron backscatter diffraction, and the transmission electron microscope, and the effect of grain-boundary orientation on slip dislocation is investigated by constructing a grain-boundary dislocation model. The results show that the anisotropy of the mechanical properties of X80 pipeline steel is related not only to grain size and microstructure type but also to grain-boundary orientation, which the obstruction effect of the high-angle grain boundary on slip dislocation is significantly greater than that of the low-angle grain boundary. The larger the orientation difference is, the more disorderly the arrangement of atoms on both sides of grain boundary is, and the more difficult it is for dislocations to slip across grain boundary, so the strengthening effect is more remarkable. Also, when the grain-boundary misorientation is greater than 15 , the strengthening effect tends to stabilize due to the influence of the interfacial superposition.