Calendering is an essential fabrication step for lithium-ion battery electrodes, aimed at achieving the target density through mechanical compression. During this process, the electrode's microstructure significantly deforms, affecting its electrochemical performance. Therefore, it is important to understand how the microstructure evolves during calendering and correlate these changes with electrochemical behavior. Despite tremendous experimental efforts, there are limitations in obtaining sufficient outcomes. In this regard, simulations offer valuable information; however, the highest priority is to develop a reliable modeling framework that reflects actual microstructural changes and establish a robust validating methodology. Without such a framework, computational predictions may not align with experimental results. This study develops a virtual calendering framework based on high-resolution FIB-SEM tomography images of a bimodal LiNi0.6Co0.2Mn0.2O2 cathode with a mass loading of 19.8 mg cm−2 and 96 wt.% active material. The framework is rigorously validated through systematically designed experiments across various electrode densities (2.3–4.0 g cm−3) and further analysis of hidden microstructural features, such as ionic tortuosity, contact area, and crack structure through additional tomography analysis. The virtual calendering framework successfully predicts microstructural changes and electrochemical performance, offering a reliable pathway for identifying optimal design parameters in a time- and cost-effective manner.