Pandemic Legacy is a co-operative campaign game, with an overarching story-arc played through 12-24 sessions, depending on how well your group does at the game. At the beginning, the game starts very similar to basic Pandemic, in which your team of disease-fighting specialists races against the clock to travel around the world, treating disease hotspots while researching cures for each of four plagues before they get out of hand.

During a player's turn, they have four actions available, with which they may travel around in the world in various ways (sometimes needing to discard a card), build structures like research stations, treat diseases (removing one cube from the board; if all cubes of a color have been removed, the disease has been eradicated), trade cards with other players, or find a cure for a disease (requiring five cards of the same color to be discarded while at a research station). Each player has a unique role with special abilities to help them at these actions.