Exploring the mechanical properties and crack characteristics of granite at the grain scale is of greatly significant to understand brittle failures, such as spalling, slabbing, and rockburst of deep-buried hard rock under high geostress. The macroscopic engineering failure of a rock mass is often closely related to the microscopic mechanical properties and microstructure of the constituent minerals. This study derived the microscopic mechanical properties of granite minerals, including Young’s modulus, hardness, fracture toughness, and stiffness ratio based on nanoindentation tests. The relationship of the micromechanical parameters including Young’s modulus, hardness, and fracture toughness is presented in the following order: quartz > K-feldspar > plagioclase > biotite. A parameter calibration process that combines nanoindentation test and trial-and-error method was then proposed to reduce the randomness in the calibration process. This calibration process was adopted to the discrete element method simulation of granite, in which the microstructure of granite is specifically defined through a Voronoi tessellation. Finally, the microcrack evolution and crack characteristics of different minerals in granite were discussed based on the micro-X-ray computed tomography, scanning electron microscopy, and numerical results. The results reveal that the intragranular cracks play a crucial role in the failure process of brittle rocks and largely dominate the macroscopic properties of materials, in which the percentage of intragranular cracks increases from 61% to more than 80% when the compression test changes to the tension test.