The western Amazon, specifically the region of Madre de Dios, is known as the biodiversity capital of Peru and is globally recognized as one of the most biodiverse places on Earth. However, it has been threatening by a serious problem of forest loss. The main environmental threats are due to mismanagement of the territory that causes the concentration of land, agricultural expansion, livestock, gold mining, and uncontrolled economic exploitation. This study analyzes the dynamics of forest loss and changes in land use and cover between 1999-2018. Remote sensing techniques were used to quantify forest loss. Landsat 5 Thematic Mapper (TM) and 8 Operational Land Imagery (OLI). The images were processed using a supervised classification called Neural Net. The methodology includes validation procedures using field verification points and medium and high-resolution remote sensing images of different sensors (SPOT-5, PlanetScope, WorldView, and Drone). The results showed a forest loss of 1698.63 km2 during 1999-2018, with an annual deforestation rate of -0.21%, and an average forest loss of 59.28 km2/year. For changes from forests to other land use, we found the conversion of 841.41 km2 during 2014-2018. Our results indicate that agriculture is the most responsible for advancing deforestation (72.90%), while gold mining has a greater incidence in targeted sectors.