In this study, an ensemble of numerical simulations with a state-of-the-art hydrodynamic model for coastal applications is used to characterize, for the first time, the expected mid-21st-century changes in circulation and associated sea-level height inside the Venice lagoon induced by projected Mediterranean sea level rise and atmospheric circulation changes over the Adriatic Sea under the RCP8.5 emission scenario. Our results show that water transports through the three inlets connecting the Venice lagoon to the open sea are expected to change significantly, with consequent significant persistent alterations of the circulation and sea-level height inside the lagoon. The projected water mass redistributions motivate further studies on the implications of climate change for the lagoon environment.