Abstract: Vapor pressure deficit (VPD) is critical to the carbon–water cycle of an ecosystem, which is widely used in various hydrological cycles, vegetation carbon cycles, and evapotranspiration-estimation models. However, few studies on VPD have been conducted. Most regions of China are experiencing accelerated urbanization and continuing increased interannual variations in atmospheric parameters, such as temperature and humidity. An in-depth study on the variation and dominant factors of VPD in different seasons and climate regions will provide a scientific basis for the study of climate, ecology, and vegetation models. Such a study will also help improve environmental management in different climate regions to achieve ecologically sustainable development. Based on the monthly meteorological observation data of more than 600 stations in China, combined with the Mann–Kendall test, multiple linear regression, and other methods, this study analyzed the spatio–temporal variation pattern of VPD in the four climate regions (i.e., arid, humid, semiarid, and subhumid) of China from 1980 to 2018 to detect the dominant meteorological factors affecting the variation of VPD. The results showed that for the last 40 years, the distribution of VPD in Chinahadd spatial and seasonal differences. For all four climate regions, VPD had the characteristics of “summer > spring > autumn > winter.” The distribution of VPD in summer and winter is opposite in the humid and arid regions of China. That is, the VPD in spring and summer gradually increased from the humid region to the arid region; whereas, it gradually decreased from the humid region to the arid region in winter. VPD exhibited an upward trend in most areas of China in the four seasons, particularly in the Yellow River Basin and southeast coastal areas in spring and summer. Moreover, the VPD of the four climate regions increased abruptly in the early 21st century. Among them, the humid region had an earlier mutation year (1996), and the arid region had a later mutation year (2004); the increase in the arid region was the highest, at approximately 0.04 kPa/10 a). These phenomena indicate that the atmosphere has become drier, and to determine the cause of this phenomenon, we analyzed the contribution rate of meteorological factors to VPD. The results showed that the dominant factors affecting the increase in VPD are different in different climate regions and seasons, but overall, changes in air temperature and absolute humidity are the main factors affecting the interannual change of VPD in China. After 2000, the dominant factors affecting VPD in subhumid and semiarid and other areas are temperature and absolute humidity, respectively.