Bone encompasses a complex arrangement of materials at different length scales, which endows it with a range of mechanical, chemical, and biological capabilities. Changes in the microstructure and characteristics of the material, as well as the accumulation of microcracks, affect the bone fracture properties. In this study, two-dimensional finite element models of the microstructure of cortical bone were considered. The eXtended Finite Element Method (XFEM) developed by Abaqus software was used for the analysis of the microcrack propagation in the model as well as for local sensitivity analysis. The stress–strain behavior obtained for the different introduced models was substantially different, confirming the importance of bone tissue microstructure for its failure behavior. Considering the role of interfaces, the results highlighted the effect of cement lines on the crack deflection path and global fracture behavior of the bone microstructure. Furthermore, bone micromorphology and areal fraction of cortical bone tissue components such as osteons, cement lines, and pores affected the bone fracture behavior; specifically, pores altered the crack propagation path since increasing porosity reduced the maximum stress needed to start crack propagation. Therefore, cement line structure, mineralization, and areal fraction are important parameters in bone fracture. The parameter-wise sensitivity analysis demonstrated that areal fraction and strain energy release rate had the greatest and the lowest effect on ultimate strength, respectively. Furthermore, the component-wise sensitivity analysis revealed that for the areal fraction parameter, pores had the greatest effect on ultimate strength, whereas for the other parameters such as elastic modulus and strain energy release rate, cement lines had the most important effect on the ultimate strength. In conclusion, the finding of the current study can help to predict the fracture mechanisms in bone by taking the morphological and material properties of its microstructure into account.