Messina 1347 takes place during the introduction of the plague epidemic, also known as the"black death", and the spreading of the infection through town. During this time, merchant ships transporting luxury goods to Europe unknowingly brought an unprecedented epidemic to these countries - and one of the first affected cities was Messina, Italy.

In the game, players take the role of hihg-standing Messina families that are leaving town and moving to the countryside out of fear of being infected by the plague. While doing this, they are trying to save other inhabitants and help in the fight against the plague infection in town. They must also endeavour to prosper in their countryside residence, where they temporarily accommodating displaced rescued residents. Everyone is there waiting there for the epidemic to subside, then they return to Messina to continue their journey to take over and dominate particular districts in the town.