During the 1980s–1990s, 4600 hectares of the seagrass Zostera marina were permanently lost from Lake Grevelingen (the Netherlands), and restoration is planned. In 1971, the lake was fully marine (salinity 30), and seagrass covered 1300 hectares. After closure in that year, the lake gradually became brackish (salinity of 23 by 1978), and the meadows expanded to 4600 hectares. However, with the creation of a sluice connection to the sea in 1978, the lake returned to marine conditions and a fatal decline initiated. We revisit traditionally suggested causes of the disappearance of the seagrass, finding them unsatisfactory. We hypothesize that during the lower salinity conditions from 1971 to 1978, selection of low-salinity genotypes occurred, and these genotypes were not adapted to returning marine conditions. This hypothesis is no longer testable through genetic analysis in Lake Grevelingen but is supported by previously unpublished experiments that found a lack of seed germination at even moderately high salinity for the now extinct population. Such processes could be relevant for, and tested in, environmentally modified water systems worldwide, particularly when isolated. Based on our assessment, the abiotic environment of Lake Grevelingen seems suitable for Z. marina restoration using a donor from a high salinity environment.