Based on Landsat TM/ETM (Thematic Mapper/Enhanced Thematic Mapper) image data from 2000 and 2010 and some other survey and statistical data, this paper first analyzed the characteristics of land use/cover change in the Manas River Basin of Xinjiang. We used numerical computation methods and index models, including land use/cover structural changes, the single land use/cover dynamic index, the land-use transfer matrix and the land use degree index, to determine the features of land use/cover change both temporally and spatially. Subsequently, the main drivers of land use/cover change and the interaction between different factors were analyzed based on a comprehensive consideration of natural factors and human factors. The findings of this study may be summarized here. (1) The land use/cover structure of this basin was dominated by unused land in both 2000 and 2010, followed by cultivated land and grassland, and lastly by water (the smallest area). The extent of land use in 2010 increased compared with that in 2000 across the whole basin. The cultivated land and built-up land increased at an accelerated rate, especially in the middle region, which at the same time resulted in a significant expansion of artificial oasis and led to an evidently decreasing trend of woodland and unused land. In the upper reaches, the most obvious change of land use/cover was the areas of grassland, glaciers and snow-covered land-a clear sign of expansion. (2) The cultivated land indicated a quite remarkable outward and inward expansion trend. According to our data for the conversion of land use/cover in 2010, the new cultivated land was mainly derived from desert shrubbery land, desert and saline-alkali land. Grassland was mostly concentrated in the upper reaches and experienced an obvious increasing trend second only to cultivated land. The increased area was mainly converted from bare rock on the mountain and piedmont desert. Built-up land also showed a noticeable increase because of the occupation of desert, cultivated land and woodland. According to our data for the change in destination of land use/cover in 2000, the reduced woodland primarily evolved to cultivated land and built-up land in the middle reaches, and to grassland and bare land in the upper reaches. Additionally, the reduced unused land was mainly transformed into artificial oasis land types. A greater proportion of bare land and sand, saline-alkali land and desert was converted into cultivated and built-up land. (3) The climate of this basin was characterized by a warming and wet trend from 1959 to 2010. Climate change was the dominant factor of land use/cover change in the upper reaches. The increase in precipitation, especially short-term heavy rainfall, might be the primary cause of the advance of glaciers and snow-covered land. In the middle reaches, the most noticeable features were the increase in cultivated and built-up land and the degradation of desert vegetation. It could be speculated that this was mainly attributable to the intensified anthropogenic activities concomitant with economic growth and the increase in population. Moreover, the reduction in gross irrigation water uptake led to an even greater reduction in return water, which led to an even greater reduction in the water needed ecologically and a degradation of natural oasis land. The evident decline in terminal lakes and serious degradation of the associated vegetation in the lower reaches are directly attributable to the combined impact of climate change and human activities.