The Ohrid-Prespa lake system is the oldest and most diverse permanent lake system in Europe, dating from the Pliocene era and aged at over 4Ma. Its smaller component is Lake Macro Prespa (thereafter called Prespa), shared by North Macedonia, Albania, and Greece. Lake Prespa’s depth was reported as 14 m mean and 48 m maximum before its major water level decline. The lake is highly sensitive to external impacts, including climate change, and has been suffering major water loss for decades. A lake-level decline of almost 10 m was documented between 1950 and 2009 due to restricted precipitation and increased water abstraction for irrigation. This study describes the changes in the surface size of Prespa Lake and the vegetation/land use in the surrounding area in the period 1984–2020 using satellite images (remote sensing, Landsat 5 & 8 images by United States Geological Survey). The lake lost 18.87 km2 of surface in this period (6.9% of its size, dropping from 273.38 km2 to 254.51 km2). Water loss was greater in the period 1987–1993 and 1998–2004. The Analysis of Normalized Difference Vegetation Index (NDVI) in the area (app. 4950 km2) surrounding Lake Prespa revealed an increase in the mean NDVI values over the period studied (1984–2020), pointing to a general increase in vegetation. Areas with NDVI > 0.13 increased from 78% in 1984 to 86% in 2020, while those with the highest vegetation intensity (NDVI > 0.45) increased by 40%. These changes in vegetation may be related to the water loss of the lake.