Lake Burullus is the second largest lake at the northern edge of the Nile Delta, Egypt, and has been recognized as an internationally significant wetland that provides a habitat for migrating birds, fish, herpetofauna, and mammals. However, the lake is experiencing severe human impacts including drainage and conversion to agricultural lands and fish farms. The primary goal of this study was to use multispectral, moderate-spatial-resolution (30 m2) Landsat satellite imagery to assess marsh loss in Lake Burullus, Egypt, in the last 35 years (1985–2020). Iterative Self-Organizing Data Analyses (ISODATA) unsupervised techniques were applied to the Landsat 5 Thematic Mapper (TM) and Landsat 8 Operational Land Imager–Thermal Infrared Sensor (OLI–TIRS) satellite images for classification of the Lake Burullus area into four main land-use classes: water, marsh, unvegetated land surfaces (roads, paths, sand sheets and dunes), and agricultural lands and fish farms. The overall classification accuracy was estimated to be 96% and the Kappa index was 0.95. Our results indicated that there is a substantial loss (44.8% loss) in the marsh aerial coverage between 1985 and 2020. The drainage and conversion of wetlands into agricultural lands and/or fish farms is concentrated primarily in the western and southern part of the lake where the surface area of the agricultural lands and/or fish farms doubled (103.2% increase) between 2000 and 2020. We recommend that land-use-policy makers and environmental government agencies raise public awareness among the local communities of Lake Burullus of the economic and environmental consequences of the alarming loss of marshland, which will likely have adverse effects on water quality and cause a reduction in the invaluable wetland-ecosystem services.