Pandemic Legacy is a co-operative campaign game, with an overall storyline played through 12-24 sessions, depending on how good your group does at the game. At the beginning, the game starts the same as the basic Pandemic, in which your team of disease-fighting specialists races against the clock to travel around the world, treating disease cities while researching cures for each of the 4 plagues before they overwhelm you.

During a player's turn, they have 4 actions, with which they can travel around in the world in multiple ways (sometimes needing to discard a card), create structures like research stations, treat diseases (taking 1 cube from the board; if all cubes of a color have been removed, the disease has been eliminated), trade cards with other players, or find a cure for a disease (requiring 5 cards of the same color to be discarded while at a research station). Each player has a different role with unique abilities to help them at these actions.

After each player has taken their actions, they draw 2 cards. These cards can have epidemic cards, which will place new disease cubes on the board, and may lead to an outbreak, spreading disease cubes even more. Outbreaks will also increase the panic level of a city, making that city more expensive to travel to.

Every month in the game, you have 2 chances to achieve that month's goals. If you are successful, you win and immediately move on to the next month. If you fail, you have another chance, with more funding for beneficial event cards.

During the campaign, new rules and elements will be introduced. These will sometimes require you to permanently change the components of the game; this may be writing on cards, ripping up cards, and putting permanent stickers on game components. Your characters can get new skills, or harmful effects. A character may even be lost completely, at which point it's no longer there for play.