Venice Lagoon (Italy), the largest wetland in the Mediterranean basin, is extremely vulnerable to variations in relative sea level (RSL) which is locally defined by an average rising rate of about 2.5 mm per year, resulting from both sea-level change and vertical land movements. The environmental pressures stemming from projected higher RSL rising rates will have a profound impact on Venetian coastal ecosystems with a significant loss of wetlands partly due to a drastic reduction of salt marsh habitats. To understand how changes in marine influence could create such ecological upheaval in the near future, and fully remodel these coastal salt marshes, we reconstructed 5650 years of RSL rise history and land subsidence impacts on ecosystem dynamics during the Holocene transgression of Venice Lagoon. We show that the evolution of ecosystems mainly mirrors the gradual intrusion of salt water that progressively reshaped the coastal vegetation by turning the area into salt lagoon habitats. Before marine influence became dominant, the area was mainly fed by substantial freshwater supplies allowing the development of a diversified alluvial vegetation. Environmental pressures increased markedly about 6800–6600 years ago when seawater began to significantly influence the area, affecting marsh-swamp ecosystems. These marine inputs promoted the spread of halophytic and salt-tolerant vegetation types which laid the foundations for what would become the current salt marsh habitats. Venice Lagoon serves as a stark reminder of how rising sea levels, accompanied by increased saltwater intrusion into freshwater habitats and adjacent lands, can drastically alter and reshape pre-existing ecosystems. The lagoon's long-term ecological record indicates that contemporary fluctuations in RSL pose a substantial ecological threat, potentially culminating in a major upheaval of aquatic habitats in the near future.