Having regard to the inherent crystal anisotropy characteristic of nickel-based single crystal and the actual industrial manufacture, and application of the turbine blade, a trade-off between orientation deviation and performance demands that attention should be paid to estimating the influences of orientation deviation from [001] to [011] on the mechanical properties of the nickel-based single crystal. The present study conducted the creep tests of nickel-based single crystals with orientation deviation under 980 °C/260 MPa and 1050 °C/169 MPa. Results show that the orientation deviation effect of nickel-based single crystals under high temperature and low stress gradually decreases with the temperature increase. A crystal plasticity finite element method based on stress, Schmid factor, γ/γ' phase, and dislocation is employed to investigate the orientation-deviation-affected creep mechanisms. The influence of orientation deviation on creep performance is summarized by combining the macroscopic mechanical properties, fracture profile morphology, and crystal plasticity finite element analysis.