The aim of this study was to establish a method for evaluating notch fatigue behavior through crystal plasticity finite element (CPFE) simulations based on the actual microstructure of the nickel-based alloy Inconel 718 (IN718). Initially, the equivalent plastic strain, εeps, which reflects the comprehensive slip at the grain scale, was employed to analyze the fatigue crack initiation mechanism of IN718, revealing that twinning and triple junctions of grain boundaries were high-risk locations for fatigue crack initiation. Next, fatigue simulations were performed on notched specimens using the CPFE model, with a material-level CPFE model particularly employed at the notch root. The increment of εeps, Δεeps, in a stable cycle was used as the fatigue damage control parameter and correlated with the fatigue life, Nf, revealing that the Δεeps-Nf relationship at material-level satisfied the form of the Mason-Coffin model. Finally, fatigue life prediction of IN718 notched specimens was carried out based on the Δεeps-Nf relationship, with the predicted results falling within the 2-fold scatter band, demonstrating good prediction accuracy.