ABSTRACT This study investigated the fatigue property of DD6 nickel‐based single crystal superalloy using in situ scanning electron microscopy (SEM), focusing on the coupled effects of secondary orientations ([010] and [110]) and recrystallization defects, representing the first comprehensive report of this synergistic interaction. Surface recrystallization significantly deteriorated fatigue resistance, with crack nucleation preferring recrystallized regions. [110]‐oriented specimens exhibited superior fatigue durability compared to [010]‐oriented counterparts in both pristine and recrystallized conditions. [010]‐oriented specimens showed pronounced cross‐slip activity, while [110]‐oriented samples maintained single‐slip deformation. Fatigue crack propagation in [010] orientation was governed by multi‐octahedral slip system activation. Combined electron backscatter diffraction (EBSD) analysis and crystal plasticity finite element modeling (CPFEM) demonstrated that [010]‐oriented specimens accumulated higher cumulative shear strain (CSS) under equivalent stress conditions compared to [110]‐oriented samples, directly correlating with reduced fatigue life. A unified fatigue life prediction model incorporating orientation and recrystallization effects was developed for cyclic loading evaluation.