Asphalt pavement is prone to fatigue cracking during long-term service, which can lead to secondary diseases and weaken the structural durability. For in-depth revelation of the fatigue damage behavior of asphalt mixtures, in this paper, a semi-circular bending (SCB) mesoscopic model was established based on the discrete element method. The fatigue fracture behavior of three typical asphalt mixtures in Jiangsu Province’s expressways, including SMA-13, SUP-20, and SUP-25, was simulated under different stress ratio conditions. The fatigue damage mechanism and evolution law of asphalt mixtures were analyzed from the aspects of fatigue life, crack propagation, and residual strength. The results show that all three mixtures exhibit typical three-stage fatigue damage characteristics, and the increase of stress ratio will significantly shorten the fatigue life and accelerate the crack development. SMA-13 shows excellent fatigue resistance due to its dense skeleton and modified asphalt mortar, followed by SUP-20, while SUP-25 performs the worst due to insufficient skeleton constraint and low mortar toughness. Meanwhile, the crack propagation paths and residual strength attenuation laws of different mixtures are significantly different, further revealing the key role of skeleton structure and asphalt mortar performance in the fatigue damage mechanism.