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In order to provide a reference for the gradation design of dense skeleton asphalt mixtures (DSAM), this study conducts a thorough analysis of the gradual meso-structural response behaviour of characteristics of the asphalt mixture main skeleton subjected to load using the digital image processing (DIP) technique. Moreover, gradation optimisation measures and the design criteria of mesoscopic evaluation indices for the main skeleton are proposed. The results indicate that aggregates with particle sizes of 2.36–4.75 mm can effectively increase the number of contact points; however, the stability of the main skeleton remains insufficient. Furthermore, coarse aggregates with a particle size larger than 4.75 mm provide the most significant contribution to the formation of a steady main skeleton; this is the critical particle size for the formation of a steadier main skeleton. Gradation is the major determinant of mesoscopic evaluation indices, including average coordination number ( n ¯ c ) and the ratio of the quantity of coarse aggregates without contact points to the total quantity of coarse aggregates (C value) for the asphalt mixture of the main skeleton. On the other hand, the performance of asphalt has an insignificant influence on mesoscopic evaluation indices; it mainly affects the development trend of macroscopic rutting. In the design process of DSAM, it is necessary to optimise gradation with the aim of increasing n ¯ c and reducing the C value so as to enhance the load resistance capacity of the primary skeleton. When preparing asphalt mixture specimens using the wheel rolling method, the design criteria for the aforementioned indices are n ¯ c ≥ 1.5 and C ≤ 15%, which can be used as bases for the design of DSAM with a nominal maximum particle size of 13.2 mm to ensure that the coarse aggregates are interlocked and form a steady main skeleton.