Sea-level rise (SLR) and flooding are among the climate change stressors challenging human society in the twenty-first century. Many coastal areas and cities are implementing innovative solutions to mitigate flood risks and enhance resilience. Venice has recently developed a system of storm surge mobile barriers, known as the MoSE (Modulo Sperimentale Elettromeccanico or Experimental Electromechanical Module). This study aims to investigate the economic viability of MoSE operations in light of the potential future evolution of SLR. To conduct a cost-benefit analysis, a system dynamics model is utilised to assess the impact of MoSE operations on economic and residential activities of Venice and its port. Simulations are conducted until the end of the century, considering two SLR scenarios. The results suggest that the economic benefits largely outweigh the combined costs of investment and foregone port revenues resulting from the MoSE closures. Nevertheless, the increasing number of closures due to SLR seriously challenges the viability of the infrastructure in the medium to long term. Even more importantly, very frequent closures will have serious impacts on the quality of the lagoon ecosystem. These findings suggest a revision and stronger integration of the city’s safeguarding strategies, including the increase of the MoSE closure level officially set at 110 cm, and other coordinated interventions, such as sewer system consolidation.