Pandemic Legacy is a co-operative campaign game, with a storyline played over 12-24 sessions, depending on how good your group does at the game. At the beginning, the game begins 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 will have 4 actions, with which they can travel around in the world in multiple ways (sometimes needing to discard a card), build structures like research stations, cure 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 assist them at these actions.

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

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

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