Cultivated land is an important indicator of landscape changes driven by human activities. Mapping the spatio-temporal changes of cultivated lands will help us to understand its corresponding environmental and ecological changes in their downstream areas. The Manas drainage basin is the key area of agricultural region in the northern slope of the Tianshan Mountains. However, the drastic farmland reclamation in the last 50 years makes irrigation water increasing rapidly, leading to environmental degradation in the downstream of the Manas River. In this paper, remote sensing and GIS technologies are used to analyze the spatio-temporal characteristics of farmland changes in the Manas drainage basin under the condition of intense soil-water utilization. Firstly, remote sensing images in 1962, 1977, 1989, 2000 and 2010 are applied to map land use changes with the cognition classification software and manual edition. Then the temporal process and spatial pattern of land cover changes are analyzed by geo-statistics and landscape analysis. On the temporal scale, the cultivated land changes and its mutual transition relationships with other land types are analyzed with areal ratio and transition matrix methods; on the spatial scale, GIS spatial analysis tool and landscape class level index are used to describe the characteristics of farmland expansion or shrinking changes in different regions and different land patches. Finally, hydrological data and irrigation construction data are used to explain the impact of climate change and human activities on the farmland landscape. The results show that: (1) The overall land use changes of the Manas drainage basin in the last 50 years are as follows: cultivated land and built-up areas increase continuously, while the unutilized land, wetland and snow/glacier have been decreasing steadily; grassland area is increasing in the former 20 years and then decreasing gradually in the last 30 years; the intensity of land use changes keeps stable after dramatic changes. (2) The overall cultivated land transformations have shifted from outward and inward transformations to single inward transformation; in inward land types, grassland and unutilized land are the main inward land types to farmland, and woodland and wetland take larger percentages in the first 20 years, while less percentages in the later 30 years; in outward land types, built-up land and grassland are the main outward land types, and grassland and unutilized land have larger percentages in the former 20 years due to cultivated land degradation; the total area of inward land types far exceeds than that of the outward land types, and the cultivated land area is steadily increasing in the last 50 years.