Machining nickel-based alloys always exhibits significant work-hardening behavior, which may help to improve the part quality by building a hardened layer on the surface, while also causing severe tool wear during machining. Hence, modeling the work-hardening phenomenon plays a critical role in the evaluation of tool wear and part quality. This paper aims to propose a numerical model to estimate the work-hardening layer for a deeper understanding of this behavior, employing both recrystallization-based and dislocation-based models to cover workpieces with multiscale grain sizes. Different user routines are implemented in the finite element method to simulate the increase in hardness in the deformed area due to recrystallization or changes in the dislocation density. The validation of the proposed model is performed with both literature and experimental data for Inconel 718 with small or large grain sizes. It is found that the recrystallization-based model is more suitable for predicting the work-hardening behavior of small-grain-size Inconel 718 and the dislocation-based model is better for that of large-grain-size Inconel 718. Further, as an important type of cutting tool in machining Inconel 718, the chamfered tools with different edge geometries are employed in the simulations of machining-induced work hardening. The results illustrate that the uncut chip thickness and chamfer angle have a significant influence on the work-hardening behavior.