In high-cycle fatigue, the majority of fatigue life is spent in the crack initiation stage. However, current models fail to accurately capture the fatigue life consumed in the crack initiation stage, resulting in discrepancies in predictions. Here, we propose a fatigue life prediction model based on the crack tip plastic zone, combined with a multi-stage crack growth approach. To quantify the crack initiation life, a modified Tanaka–Mura model is developed by incorporating the effects of localized plastic deformation at the crack tip. The proposed model demonstrates good agreement with experimental observations. Furthermore, a reliability-based fatigue evaluation framework is established by introducing a fatigue safety factor formulation. The results show that the safety factor decreases with increasing applied stress levels, attributed to the reduced standard deviation and lower scatter of fatigue life at higher stresses. The findings provide a practical and physics-informed methodology for fatigue life and safety assessment of aluminum alloy components under complex cyclic loading conditions.