The climatic extremes and the dynamics of land use and cover can cause changes in river flow. The objective of this work was to analyze the flow of the Araguaia River under the effects of extreme years associated with the dynamics of land use in the Araguaia Watershed (AW) from 1981 to 2019. The land use and land cover product were based on the MapBiomas Project classification, imported from the Google Earth Engine. The measured rainfall and flow data were obtained from the National Water Agency. In contrast, the estimated rainfall was based on the data Climate Hazards Group InfraRed Precipitation with Stations. The precipitation climatology showed the lowest values (1,464.9–1,720.4 mm) in the south-central sector, and the highest (1,720.4–2,014.6 mm) rainfall amounts were observed in the north sector. However, it was identified in the five pluviometric stations with a high variability of precipitation, with an emphasis on the extreme years. Such wet and dry years were marked by a large difference in water availability. There was an intense reduction of the Amazon and Cerrado biomes by 31,641.8 and 42,618.9 km², respectively, mainly due to the expansion of 18,936.1 km² of agricultural activities and 47,494 km² of pasture. The fluviometric variability showed a decreasing trend, mainly in the past 15 years. Public actions, such as the intensification of environmental policies, monitoring focusing on the most compromised and strategic areas such as the headwaters of the Araguaia River, can minimize the impacts caused by climate extremes and deforestation.