Aimed at research the deformation orientation in VHCF regime under different temperatures, fatigue behavior of [111]-oriented DD6 single crystal superalloy at 1000 °C and 760 °C was studied. Using the stress range criterion, the [111] orientation shows higher fatigue resistance. This difference decreases with lower stress ranges and almost vanishes near 109 cycles. In contrast, the [111] orientation has lower fatigue resistance than the [001] orientation by using the total strain range criterion. Dislocations are restricted from shearing the γ’ phase due to the lower octahedral resolved shear stress in the [111]-oriented, decreasing the deformation in γ’ phase. Combined with distinctive cross-slip behavior, this further increased the deformation along the γ-channel, significantly enhancing deformation inhomogeneity between the γ’ phase and γ-channels. At elevated temperatures, thermally activated dislocation climb and higher climb stress factor lead to a greater reduction in fatigue performance for [111] orientation at lower stress level.