Lake Poopó is located in the Andean Mountain Range Plateau or Altiplano. A general decline in the lake water level has been observed in the last two decades, coinciding roughly with an intensification of agriculture exploitation, such as quinoa crops. Several factors have been linked with the shrinkage of the lake, including climate change, increased irrigation, mining extraction and population growth. Being an endorheic catchment, evapotranspiration (ET) losses are expected to be the main water output mechanism and previous studies demonstrated ET increases using Earth observation (EO) data. In this study, we seek to build upon these earlier findings by analyzing an ET time series dataset of higher spatial and temporal resolution, in conjunction with land cover and precipitation data. More specifically, we performed a spatio-temporal analysis, focusing on wet and dry periods, that showed that ET changes occur primarily in the wet period, while the dry period is approximately stationary. An analysis of vegetation trends performed using 500 MODIS vegetation index products (NDVI) also showed an overall increasing trend during the wet period. Analysis of NDVI and ET across land cover types showed that only croplands had experienced an increase in NDVI and ET losses, while natural covers showed either constant or decreasing NDVI trends together with increases in ET. The larger increase in vegetation and ET losses over agricultural regions, strongly suggests that cropping practices exacerbated water losses in these areas. This quantification provides essential information for the sustainable planning of water resources and land uses in the catchment. Finally, we examined the spatio-temporal trends of the precipitation using the newly available Climate Hazards Group Infrared Precipitation with Stations (CHIRPS-v2) product, which we validated with onsite rainfall measurements. When integrated over the entire catchment, precipitation and ET showed an average increasing trend of 5.2 mm yr−1 and 4.3 mm yr−1, respectively. This result suggests that, despite the increased ET losses, the catchment-wide water storage should have been offset by the higher precipitation. However, this result is only applicable to the catchment-wide water balance, and the location of water may have been altered (e.g., by river abstractions or by the creation of impoundments) to the detriment of the Lake Poopó downstream.