The comminution process and mechanism of low-grade hematite ore in a high pressure grinding roll (HPGR) were investigated in this work. Three different methods were used for comminution of the hematite ore: HPGR with an air classifier, HPGR with screening followed by ball milling (HPGR+BM), and cone crushing with screening followed by ball milling (CC+BM). In addition, the effects of comminution methods on the degree of liberation of minerals in the grinding products were compared. The results suggest that the comminution process of the ore can be divided into four stages: appearance of tiny cracks, expansion of tiny cracks, which eventually form microcosmic cracks, development of principle cracks, and generation of the conjugate fracturing zone. Intergranular cracks, including partial intergranular cracks and complete intergranular cracks, are apparent in the comminution products of the HPGR. The complete intergranular cracks mainly occur in the conjugate fracturing zone, while the partial intergranular cracks within the particles result in an abundance of locked-particles in the comminution products. Furthermore, the degree of liberation of minerals is more influenced by the final grinding mode rather than the crushing method. It is found that complete intergranular cracks in the conjugate fracturing zone play a significant role in increasing the degree of liberation of iron minerals in the fine size fraction. The “mosaic-type” locked-particles have negligible effect on the liberation properties of iron minerals during the subsequent grinding process.