Human settlements in arid areas are restricted by the areas’ natural drought condition, which shows an obvious characteristic of system imbalance. Therefore, promoting system coupling and coordination is important for the construction of human settlements in arid areas. To explore the spatiotemporal evolution mechanism of the human settlements in arid areas from the perspective of system coupling coordination, this study considers the human settlements of 14 administrative regions of prefecture level in Xinjiang, China as the research object. An evaluation system is created for the coordinated development of human settlements in arid areas. Based on the coupling coordination degree model of five subsystems, this study comprehensively uses the entropy method, GIS spatial analysis, and structural equation model to explore the spatiotemporal evolution law and coupling mechanism of the coupling coordination degree of the human settlements system in Xinjiang from 2003 to 2019. The results show the following: (1) Time dimension: from 2003 to 2019, the coupling degree and coupling coordination degree of the human settlements system in Xinjiang showed a fluctuating upward trend, and the growth rate was uneven among the 14 administrative regions of prefecture level. (2) Spatial dimension: forming the spatial distribution pattern of “high in the middle, low on both sides, high in the north and low in the south”, evolving from “one-line type” to “inverted U type” in the east-west direction, and from “one-line type” to “U type” and then to “oblique line type” in the north-south direction. (3) Mechanism of action: mainly formed the path of “human system→social system→residential system→support system”, and “social system→natural system”, the effect is respectively 0.570, 0.972, 0.953, and -1.189. Among them, the human system is the fundamental driving force for the coordinated development of human settlements in arid areas, and affects other systems positively or negatively through the social system.