In this work, a mechanistic model is proposed for ion-irradiated nanocrystalline (NC) metals to characterize the evolution of hardness as a function of the indentation depth at room temperature and under quasi-static loading condition. At the grain level, grain interiors (GIs) and grain boundaries (GBs)-dominated hardening are addressed simultaneously in the developed model, which is able to effectively characterize the contribution of geometrically necessary dislocations (GNDs), statistically stored dislocations (SSDs), irradiation-induced defects, Hall-Petch effect and the intrinsic strength of GBs. Thereinto, the GIs-dominated hardening mechanisms are systematically analyzed by considering the evolution of microstructures, which include the average density of dislocations and irradiation-induced defects within the plastic zone, and are noticed to be affected by the high ratio of GBs. Main attentions are focused on the description of GBs influence that covers dislocation hardening and defect hardening. The rationality and accuracy of the proposed model are validated by comparing the theoretical results with corresponding experimental data under different irradiation conditions. The proposed model offers a promising way to analyze the irradiation hardening mechanisms of NC metals.