The underlying phenomenology of the crystallographic orientation dependence on ferroelectric fatigue behavior was investigated in rhombohedral Pb(Zn1∕3Nb2∕3)O3-5%PbTiO3 (PZN-5PT) crystals. It was recently found that an electric field (E field) application along the ⟨001⟩ direction of PZN-5PT crystal did not induce the fatigue to 105cycles of bipolar electric field cycling (switching), while the ferroelectric fatigue became evident from 103cycles of polarization switching along the ⟨111⟩ direction. In this study, the dependence of ferroelectric fatigue on the crystal orientation is explained by changes in internal stress, switching mechanisms, and domain configuration. The magnitude of the in-plane tensile strain was a maximum during a domain switching in ⟨111⟩ oriented crystals, resulting in the suppressed motion of domain boundaries in ⟨111⟩ oriented crystals. In addition to the stress, differences in domain switching mechanisms and domain boundary density for ⟨001⟩ and ⟨111⟩ oriented crystals contributed to the orientation dependence of ferroelectric fatigue. Sideways domain growth became dominant and domain width increased when the E field was applied along the ⟨111⟩ direction. Sideways domain growth of ⟨111⟩ oriented crystal swept oxygen vacancies of the domains during the consecutive switching process, leading to the effective accumulation of oxygen vacancies at the domain boundaries. Smaller domain boundary densities found in ⟨111⟩ oriented crystals, in comparison to ⟨100⟩ oriented crystals, also contributed to the increase in the density of accumulated oxygen vacancies at domain boundaries after sweeping oxygen vacancies of the domains, due to the impact of increased E-field cycling and cumulative switching. High in-plane tensile stress and a high concentration of oxygen vacancies at the domain boundaries due to sideways growth and small domain boundary density were suggested to pin the movement of domain boundaries and enhance the fatigue in ⟨111⟩ oriented crystals.