In this study, we show the complexity associated with the recent land cover changes by elucidating the paths of 30 years of changes in the Upper Paraná River Basin (UPRB), a region severely impacted by agricultural activity, one of the areas with the highest density in the production of hydroelectricity, biofuels and food in the world. In this sense, a post-classification comparison approach based on Landsat images was used to identify detailed ‘from-to’ paths behind those land cover changes. The most expressive changes were the expansion of Cropland and Forest areas and the reduction in savannas, with a net change of 17.9%, 4.1%, and −16.9% of the UPRB area, respectively. Cropland areas showed an expressive increase between 1985 and 2015, rising from 249,439 km2 (27.7%) to 412,909 km2 (45.9%). Forest areas increased from 149,389 km2 to 185,839 km2 in the period. Notably, for this class, an intense spatial dynamic of losses (7.5%) and gains (11.6%) took place between 1985 and 2015. This behavior is related to the disappearance of native vegetation fragments in some sub-basins, as well as to afforestation, reforestation, and/or forest restoration in others. The Cerrado (a typical tropical savanna in South America), the most impacted natural biome of the Basin, decreased from 21.9% of the UPRB in 1985 (196,746 km2) to only about 5% of the whole UPRB area in 2015. Grassland areas, mostly used for livestock, decreased from 271,827 km2 (30.2%) to 229,007 km2 (25.5%). This net decrease was associated with a reduction of 160,830 km2 (17.8%) and the appearance of 118,010 km2 (13.2%) in new areas, previously occupied by tropical savannas in 1985. In conclusion, economic factors were the main drivers for land cover changes, especially agriculture and livestock activities, besides forestry and hydroelectric energy production. In addition, Grassland areas that predominated on the left banks of the UPRB in 1985 retreated with the advance of Cropland areas, mainly due to the expansion of sugarcane for ethanol production, a biofuel widely used in Brazil. In turn, pasture areas migrated to the right bank and occupied a significant part of the Cerrado. Finally, our results demonstrate that the transition dynamics among land cover classes can involve complex political-economical mechanisms that are not always captured by remote sensing.