In Pandemic, several virulent diseases have broken out simultaneously all over the world! The players are disease-fighting specialists whose mission is to treat disease hotspots while researching cures for each of four plagues before they get out of hand.

The game board depicts several major population centers on Earth. On each turn, a player can use up to four actions to travel between cities, treat infected populaces, discover a cure, or build a research station. A deck of cards provides the players with these abilities, but sprinkled throughout this deck are Epidemic! cards that accelerate and intensify the diseases' activity. A second, separate deck of cards controls the "normal" spread of the infections.

Taking a unique role within the team, players must plan their strategy to mesh with their specialists' strengths in order to conquer the diseases. For example, the Operations Expert can build research stations which are needed to find cures for the diseases and which allow for greater mobility between cities; the Scientist needs only four cards of a particular disease to cure it instead of the normal five—but the diseases are spreading quickly and time is running out. If one or more diseases spreads beyond recovery or if too much time elapses, the players all lose. If they cure the four diseases, they all win!

The 2013 edition of Pandemic includes two new characters—the Contingency Planner and the Quarantine Specialist—not available in earlier editions of the game.

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.

After a player has taken their actions, they draw two cards. These cards can include epidemic cards, which will place new disease cubes on the board, and can lead to an outbreak, spreading disease cubes even further. Outbreaks additionally increase the panic level of a city, making that city more expensive to travel to.

Each month in the game, you have two chances to achieve that month's objectives. If you succeed, you win and immediately move on to the next month. If you fail, you have a second chance, with more funding for beneficial event cards.

During the campaign, new rules and components will be introduced. These will sometimes require you to permanently alter the components of the game; this includes writing on cards, ripping up cards, and placing permanent stickers on components. Your characters can gain new skills, or detrimental effects. A character can even be lost entirely, at which point it's no longer available for play.