The Marsili Seamount (Tyrrhenian Sea, Italy) is the largest submarine volcano in the Mediterranean Sea, located in the middle of the Marsili Basin, facing the Calabrian and Sicilian coasts on its eastern side, and the coasts of Sardinia on the opposite side. It has erupted in historical times, and its summit crest is affected by widespread hydrothermal activity. This study looks at mass failures taking place at different depths on the flanks of the volcano and estimates their associated tsunamigenic potential. Mass failure, tsunami generation, and propagation have been simulated by means of numerical models developed by the Tsunami Research Team of the University of Bologna. In all, we consider five cases. Of these, three scenarios, one regarding a very small detachment and two medium-sized ones (between 2 and 3 km3 failure volume), have been suggested as possible failure occurrences in the published literature on a morphological basis and involve the north-eastern and north-western sectors of the volcano. The two additional cases, one medium-sized and one extreme, intended as a possible worst-case scenario (volume 17.6 km3), affecting the eastern flank. Results indicate that small-volume failures are not able to produce significant tsunamis; medium-size failures can produce tsunamis which dangerously affect the coasts if their detachment occurs in shallow water, i.e., involves the volcano crest; and extreme volume failures have the potential to create disastrous tsunamis. In all the simulations, tsunami waves appear to reach the Aeolian Islands in around 10 min and the coasts of Calabria and Sicily in 20 min. This study highlights that there is a potential for dangerous tsunamis generation from collapses of the Marsili volcano and as a consequence a need to intensify research on its status and stability conditions. More broadly, this investigation should also be extended to the other volcanic seamounts of the Tyrrhenian Sea, since their eruptive style, evolution, and tsunamigenic potential are still poorly known.