A grain-based model (GBM) was established based on the results of uniaxial compression test by discrete element method. The intragranular and intergranular contact model of GBM was improved according to the results of indoor cyclic loading and unloading tests. A grain-based reinforcement model was established, which accurately characterized the cyclic loading strengthening effect. The grain-based reinforcement model was used to reveal the influence mechanism of cyclic loading strengthening on the mesoscopic failure of granite during uniaxial compression. The results showed that the stress distribution by self-locking effect was different in the pre-peak stress stage, which led to tensile microcracks in intergranular and intragranular contact. The Quartz and feldspar became load-bearing bodies in turn. The shear energy by the earlier strengthening was released in the post-peak stress stage, leading to the intensive intergranular microcracks of feldspar. The phenomenon was the main sign of the instability of the specimen. The differential failure of the minerals around the feldspar caused the change of the feldspar destruction pathways and the peak stress of test block increased with the enlargement of strengthening factor. The grain-based reinforcement model provides a new method, which is used to study the mesoscopic failure mechanism of brittle rocks with different loading paths on cyclic loading strengthening.