Abstract: High-quality development of the Yangtze River Economic Belt with the promotion of comprehensive economic strength as the core is the key to achieve a new era of regional coordination pattern. Based on this, a regional economic comprehensive level measurement system was constructed in this paper. The spatiotemporal evolution characteristics and the driving mechanisms of the regional economic comprehensive level of the Yangtze River Economic Belt were analyzed from a multi-scale and multi-mechanism perspective from 2001 to 2020. The results indicated that: (1) Regional economic differences showed a fluctuating downward trend, with scale differences of provincial-level>prefecture level>district level, which indicated a significant imbalance in regional economic development at the provincial level. Internal development at the prefecture level was shown as relatively balanced. (2) The development of regional economy showed a positive agglomeration feature, with obvious regional scale effects and strong spatial correlation pattern stability. There was a circular hot and cold point agglomeration distribution from downstream to upstream; The spatial classification was mainly based on low to medium level areas, with a distribution pattern of planar agglomeration and point inlay from low to high levels; Path dependent was the subject of spatial evolution. (3) The spatial differentiation of regional economy was obvious, exhibiting agglomeration characteristics. The development level of coastal and riverside cities was relatively high; In term of clustering characteristics, urban agglomerations had a higher development; In terms of hierarchical characteristics, the higher administrative level of a city had a better development; In term of functional characteristics, comprehensive cities were superior to resource-based cities; In terms of stepped features, the eastern cities were superior to the central and western regions. (4) Multiple factors of location, economy, society, and politics acted together in influencing the spatiotemporal evolution of regional economic differences at different spatial scales. (5) The high-quality development of the economic belt economy should resolve issues of making systematic improvement to promote overall regional development, implementing economic belt strategy to promote regional spatial coordination, and strengthening regional policies to promote high-quality development.