As a typical ecological fragile area, Northwest China is marked by drought and dust climate. Vegetation is known as an indicator of the terrestrial ecosystems response to climate change. In th paper, the normalized difference vegetation index (NDVI) from 1999 to 2010 and meteorological data are employed to investigate the spatiotemporal variation of vegetation cover over Northwest China, and the effects of human activities and climate change on vegetation cover change were also analyzed by using Sen-trend combined with the Mann-Kendall test, correlation and partial correlation analysis and residual method. The results showed that the vegetation coverage presented an increasing trend over Northwest China, but the vegetation growth was still hindered in some areas. The spatial difference of vegetation cover change may be the results of the interaction between human activities and climate change. Vegetation cover was significantly correlated with climatic factors in most area. Whats more, the response of vegetation cover change to temperature and precipitation had a lag time. Evapotranspiration was greater than precipitation, and human irrigation had to make up for the lack of water, which made agricultural vegetation area increase. The vegetation cover decreased in Northern Xinjiang due to drought and desertification, human activities and urban expansion also inhibited the growth of vegetation seriously.