The wetland ecosystem in the "Three-River Headwaters" (TRH) region plays an irreplaceable role in water source conservation, run-off adjustment and biodiversity maintenance. In recent years, assessment of wetland resources affected by climate changes has aroused enormous attention, since it can further protect wetland resources and provide a scientific basis for decision makers. In this study, wetland changes and its response to climate changes in the TRH region from the early 1990s to 2012 were analyzed by remote sensing (RS) image interpretation and climate change trend analysis. The results showed that wetlands occupied 6.3% of the total land area in 2012, and swamps, streams & rivers and lakes were the dominant wetland types in the TRH region. Since the early 1990s, wetlands have undergone great changes, and total wetland area increased by 260.57 km(2) (1.17%). Lakes, reservoir & ponds took on continuous increasing trend, but swamps, streams & rivers had a continuous decreasing trend. On the other hand, the wetland area in the Yangtze River basin showed an overall increasing trend, while in the Yellow River and Langcang River basins, it decreased in general. The climate turned from Warm-Dry to Warm-Wet. The average temperature and precipitation increased by 0.91 degrees C and 101.99 mm, respectively, from 1990 to 2012, and the average humidity index (HI) increased by 0.06 and showing an upward trend and a shifting of the dividing line towards the northwest in both the areas of semi-humid and semi-arid zone. The correlation analysis of wetland changes with meteorological factors from 1990 to 2012 indicated that the regional humidity differences and the interannual variation trend, caused by the change of precipitation and evaporation, was the main driving factor for the dynamic variation of wetland change in the TRH region. In the general, the increase of HI in the THR region since the 1990s, especially in the western TRH region, contributed to wetland increase continuously. The conclusions of this study will provide some scientific references for the management and protection of wetlands in the TRH region, especially for restoration, reconstruction and conservation of degradation wetland.