Sensitivity assessment is useful for monitoring land desertification. Research into how to prevent and control desertification is also important. In the arid region of northwest China, desertification is becoming worse and is a serious problem that affects local sustainable development. Based on remote-sensing and geographic information system technology, this study establishes a “soil-terrain-hydrology-climate-vegetation” desertification sensitivity comprehensive evaluation system to reflect the spatiotemporal changes of land desertification, and proposes a spatial distance model to calculate a desertification sensitivity index. The spatiotemporal change characteristics of land desertification sensitivity in northwest China are quantitatively assessed from 2000 to 2017. Moreover, the main driving factors are analyzed using the geographical detector method. The results show the following. (1) Terrain, soil, climate, vegetation and hydrology affect and restrict each other, and constitute the background conditions of the distributions and changes of sensitivity to desertification in northwest China. (2) Desertification sensitivity generally displays a low distribution characteristic on the periphery of the area and a high one in the interior. The low-sensitivity regions are mainly in the five major mountain ranges (Altai Mountains, Tianshan Mountains, Kunlun Mountains, Altun Mountains and Qilian Mountains), while the high-sensitivity regions are mainly in regions such as the Junggar Basin, the Tarim Basin and the Inner Mongolia Plateau, as well as the Taklimakan Desert, Badain Jaran Desert and Tengger Desert. The spatial distribution of desertification sensitivity is obviously regional, and the high- and low-sensitivity regions have clear boundaries and a concentrated distribution. (3) With regard to spatiotemporal evolution, changes in desertification sensitivity since 2000 have been predominantly stable, and the overall sensitivity has displayed a slowly decreasing trend, indicating that potential desertification regions are decreasing annually and that some achievements have been made in the control of regional desertification. (4) Soil and climate play a direct role in the driving factors of desertification in northwest China, and these have been found to be the most important influential factors. Vegetation is the most active and basic factor in changing the sensitivity. In addition, topography and hydrology play a role in restricting desertification changes. Socio-economic factors are the most rapid factors affecting regional desertification sensitivity, and their impacts tend to be gradually increasing. In general, desertification has been effectively controlled in northwest China, and positive results have been achieved in such control. However, against the backdrop of intensified global climate change, increasingly prominent human activities and new normals of socio-economic development, the monitoring, assessment and control of desertification in China still have a long way to go.