The effects of misorientation on the quasi-static and dynamic mechanical behaviors of a second generation Ni-based single crystal superalloy DD5 were investigated. A Split-Hopkinson pressure bar system was used to perform dynamic compression. The crystallographic misorientation between the stress axis and the  direction was characterized through rotating orientation X-ray diffraction. The results demonstrated that the flow stress was closely related to the misorientation. It decreased first and consequently increased as the misorientation increased from 0° to 45°. The dynamic flow stress was significantly higher than the quasi-static stress. Moreover, the flow stress under dynamics was more sensitive to the misorientation. A constitutive model was used to illustrate the misorientation effect on the mechanical behavior. Finally, the effect of strain rate on the crystal orientation was also investigated. It was discovered that the orientation deviation change following quasi-static compression could be neglected. By contrast, the orientation changed by 3–9° subsequently to dynamic compression.