The expansion of urban construction land in Xinjiang, the Core Area of the Silk Road Economic Belt, was analyzed as comprising a spatio-temporal change system. Information regarding land use change over 7 years from 1980 to 2015 was extracted. Using a 10 km×10 km grid, the spatial and temporal evolution characteristics of land use expansion were comprehensively assessed from the viewpoints of the gross trend, sub-prefecture-level regions, sub-land types and distinctiveness. Using the Geographical Detector model, the degree of influence of human and natural elements of urban construction land expansion and the interaction between various elements were quantitatively diagnosed at the county level. Then, the main control elements were identified and their mechanism of action discussed. The differentiation between the two key development areas of the Tianshan North-slope urban agglomeration and Kashgar metropolitan region was analyzed. The results showed that, over the past 35 years, urban construction land in Xinjiang had expanded by about 2.9 times. The intensity of the expansion fluctuated, and expansion was dominated by scattered small patches. There were significant spatial and temporal differences in the scale and intensity of the expansion in various regions. The expansion of urban land and other construction land presented dynamic change characteristics. The distinctiveness of urban construction land expansion were affected by natural background constraints and economic and social development. At the county level, the low-level expansion of urban construction land and human and natural factors at all levels was the main spatial coupling and matching relationship over the entire study area. Based on the results of the factor analysis module and interaction module of the Geographic Detector, it was concluded that terrain niche index, urbanization rate, landform relief degree, and the proportion of secondary and tertiary industries were the main controlling factors affecting the expansion of urban construction land in Xinjiang. The underlying mechanisms of the main control factors were also explored. There were similarities and differences in driving factors in the key development areas, the Tianshan North-slope urban agglomeration and Kashgar metropolitan region. The present study provides scientific support and a basis for decision-making for the sustainable development of Xinjiang and the differential regulation of urban construction land due to different locations, cities, and sub-land types.