Estuarine water bodies provide a land to sea (freshwater to saltwater) transition zone. Protected from the full force of waves, winds, and storms by topographic features, e.g., reefs and barrier islands, estuaries provide habitats for countless numbers of plant and animal species. An estuary's wetlands, including salt marshes, naturally improve water quality by acting as filters. Thus, there are societal benefits to preserving estuaries. The U.S. government, in fact, passed the Coastal Zone Management Act of 1972, creating the National Estuarine Research Reserve (NERR) System. The present study documents temporal land cover change occurring during the period 1974–2001 within the Grand Bay National Estuarine Research Reserve (GBNERR)—the 24th NERR, designated in 1999. Occupying an area of 7284 hectares, it is one of the largest relatively undisturbed estuarine marsh–pine savanna habitats remaining on the northern coast of the Gulf of Mexico. Results were obtained by applying both unsupervised classification and change detection techniques to data derived from Landsat satellite imagery acquired in 1974, 1991, and 2001, respectively. Land cover classes included open water, herbaceous wetland, forest, and barren land. For change detection analysis, change matrices were derived from postclassified pairs of successive image dates, yielding two change matrices. A map of overall cover change between 1974 and 2001 was also produced. Submersion of wetlands by water, attributed to a combination of factors, including rising sea levels, land subsidence, and historical geomorphologic changes that increased wave action and decreased sedimentation, caused a majority of the observed changes. Such a broad land cover analysis provides resource managers with information regarding the estuary's land cover types and spatial distributions, allowing for more informed decisions with regard to preserving biodiversity and planning restoration efforts.