It is important to determine long-term changes in vegetation cover, and the associated driving forces, to better understand the natural and human-induced factors affecting vegetation growth. We calculated the fractional vegetation coverage (FVC) of the Urumqi River basin and selected seven natural factors (the clay and sand contents of surface soils, elevation, aspect, slope, precipitation and temperature) and one human factor (land use type). We then used the Sen–Man–Kendall method to calculate the changing trend of the FVC from 2000 to 2020. We used the optimal parameters-based geographical detector (OPGD) model to quantitatively analyze the influence of each factor on the change in vegetation coverage in the basin. The FVC of the Urumqi River basin fluctuated from 2000 to 2020, with average values between 0.22 and 0.33. The areas with no and low vegetation coverage accounted for two-thirds of the total area, whereas the areas with a medium, medium–high and high FVC accounted for one-third of the total area. The upper reaches of the river basin are glacial and forest areas with no vegetation coverage and a high FVC. The middle reaches are concentrated in areas of urban construction with a medium FVC. The lower reaches are in unstable farmland with a medium and high FVC and deserts with a low FVC and no vegetation. From the perspective of the change trend, the areas with an improved FVC accounted for 62.54% of the basin, stable areas accounted for 5.66% and degraded areas accounted for 31.8%. The FVC showed an increasing trend in the study area. The improvement was mainly in the areas of urban construction and desert. Degradation occurred in the high-elevation areas, whereas the transitional zone was unchanged. The analysis of driving forces showed that the human factor explained more of the changes in the FVC than the natural factors in the order: land use type (0.244) > temperature (0.216) > elevation (0.205) > soil clay content (0.172) > precipitation (0.163) > soil sand content (0.138) > slope (0.059) > aspect (0.014). Apart from aspect, the explanatory power (Q value) of the interaction of each factor was higher than that of the single factor. Risk detection showed that each factor had an interval in which the change in the FVC was inhibited or promoted. The optimum elevation interval of the study area was 1300–2700 m and the greatest inhibition of the FVC was seen above 3540 m. Too much or too little precipitation inhibited vegetation coverage.