The aim of this study was to build an in silico computer-aided design and computer-aided manufacturing (CAD/CAM) resin-composite-block (RCB) model with different silane coupling ratios and to evaluate the physical and mechanical properties of the models, including the elastic modulus, Poisson’s ratio, compressive strength, and maximum principal strain. Nanoscale CAD/CAM RCB models were designed by using CAD software that consisted of twelve spherical silica nanofiller particles and a resin matrix. Seven nanoscale models with different silane coupling ratios were prepared with the same filler volume contents. Homogenization analysis was conducted by using voxel-base finite-element analysis software to predict the elastic moduli and Poisson’s ratio of the macro CAD/CAM RCB. Localization analysis was used to analyze the maximum principal strain distribution in the hydrolysis layer. In silico multi-scale analysis demonstrated that the compressive strength of the CAD/CAM RCB was reduced with a decrease in the silane coupling ratios of the fillers.