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Land use/land cover change and climate change have diverse impacts on the water resources of river basins. This study investigated the trends of climate change and land use/land cover change in the Nile River Basin. The climate trends were analyzed using the Mann–Kendall test, Sen’s slope estimator test and an innovative trend analysis method. Land use/land cover (LULC) change was examined using Landsat Thematic Mapper (TM) and Landsat Enhanced Thematic Mapper (ETM+) with a resolution of 30 m during 2012–2022. The findings revealed that forestland and shrub land area decreased by 5.18 and 2.39%, respectively. On the other hand, area of grassland, cropland, settlements and water bodies increased by 1.56, 6.18, 0.05 and 0.11%, respectively. A significant increasing trend in precipitation was observed at the Gondar (Z = 1.69) and Motta (Z = 0.93) stations. However, the trend was decreasing at the Adet (Z = −0.32), Dangla (Z = −0.37) and Bahir Dar stations. The trend in temperature increased at all stations. The significant changes in land use/land cover may be caused by human-induced activities in the basin.