Investigating fatigue failure in titanium alloys is crucial for material design and engineering. Fatigue behavior in dual‐phase titanium alloys is strongly correlated with microstructural features and microdefects. This work formulates an improved modeling method to investigate fatigue behavior of bimodal Ti–6Al–4V, emphasizing the effects of lamellar orientation and microdefects. Using an improved Voronoi tessellation method, we establish representative volume element (RVE) models with various grain size distributions. Crystal plasticity finite element modeling (CPFEM) is used to analyze fatigue deformation in bimodal Ti–6Al–4V, considering microdefects and lamellar orientation. Fatigue indicator parameters are then incorporated into CPFEM to predict fatigue life and verified with experimental data. Numerical results highlight the significant influence of lamellar orientation and microdefects on fatigue behavior, with predicted life within the 3‐error band. This method efficiently overcomes challenges in quantitatively characterizing microstructural lamellae that experiments are short of, paving the way for designing fatigue‐resistant alloy materials with similar microstructures.