The anisotropic fatigue properties of three Ni-based SX superalloys (AM1, CMSX-4 and MC-NG) were investigated in the very high cycle fatigue regime at 20 kHz, R = −1 and 750 °C. The fatigue testing shows that the [111] orientation has higher fatigue lives at high stresses and lower fatigue lives at very low stresses compared to the standard [001] orientation. At high stresses, the resolved shear stress on the octahedral slip systems explains the anisotropy effect. At low stresses, pseudo-cube slip in the matrix becomes the prominent deformation mechanism over γ′-shearing in the [111] orientation, resulting in comparatively lower fatigue properties.