Granite exhibits obvious meso-geometric heterogeneity. To study the influence of grain size and preferred grain orientation on the damage evolution and mechanical properties of granite, as well as to reveal the inner link between grain size‚ preferred orientation, uniaxial tensile strength (UTS) and damage evolution, a series of Brazilian splitting tests were carried out based on the combined finite-discrete element method (FDEM), grain-based model (GBM) and inverse Monte Carlo (IMC) algorithm. The main conclusions are as follows: (1) Mineral grain significantly influences the crack propagation paths, and the GBM can capture the location of fracture section more accurately than the conventional model. (2) Shear cracks occur near the loading area, while tensile and tensile-shear mixed cracks occur far from the loading area. The applied stress must overcome the tensile strength of the grain interface contacts. (3) The UTS and the ratio of the number of intergrain tensile cracks to the number of intragrain tensile cracks are negatively related to the grain size. (4) With the increase of the preferred grain orientation, the UTS presents a “V-shaped” characteristic distribution. (5) During the whole process of splitting simulation, shear microcracks play the dominant role in energy release; particularly, they occur in later stage. This novel framework, which can reveal the control mechanism of brittle rock heterogeneity on continuous-discontinuous trans-scale fracture process and microscopic rock behaviour, provides an effective technology and numerical analysis method for characterizing rock meso-structure. Accordingly, the research results can provide a useful reference for the prediction of heterogeneous rock mechanical properties and the stability control of engineering rock masses.