The Shule River Basin (SRB) is a typical arid area in northwest China with a fragile ecology. Understanding vegetation dynamics and its response to climate change and human activities provides essential ecological and environmental resource management information. This study extracted fractional vegetation coverage (FVC) data from 2000 to 2019 using the Google Earth Engine platform and Landsat satellite images, employing trend analysis and other methods to examine spatiotemporal changes in vegetation in the SRB. Additionally, we used partial correlation and residual analyses to explore the response of FVC to climate change and human activities. The main results were: (1) The regional average FVC in the SRB showed a significant upward trend from 2000 to 2019, increasing by 1.3 × 10−3 a–1. The area within 1 km of roads experienced a higher increase of 3 × 10−3 a–1, while the roadless areas experienced a lower increase of 1.1 × 10−3 a–1. The FVC spatial heterogeneity in the SRB is significant. (2) Partial correlation analysis shows that the FVC correlates positively with precipitation and surface water area, with correlation coefficients of 0.575 and 0.744, respectively. A weak negative correlation exists between the FVC and land surface temperature (LST). FVC changes are more influenced by precipitation than by LST. (3) The contributions of climate change to vegetation recovery are increasing. Human activities, particularly agricultural practices, infrastructure development, and the conversion of farmland to grassland, significantly influence vegetation changes in densely populated areas. (4) The area changes of different land types are closely related to climate factors and human activities. Increased construction, agricultural activity, and converting farmland back to grassland have led to an increase in the area proportions of “impervious surfaces”, “cropland”, and “grassland”. Climate changes, such as increased rainfall, have resulted in larger areas of “wetlands” and “sparse vegetation”. These results provide valuable information for ecosystem restoration and environmental protection in the SRB.