In 2016, one of the most popular names used by players for their virus was 'Trump', according to the game's developer, Ndemic Creations. This is a reference to presidential candidate Donald Trump.

James Vaughn, the game's developer, was invited to speak at the Center of Disease Control, or CDC for short, in March 2013. Vaughn spoke about how he modeled the spread of infection in the game as well as how Plague Inc. can raise awareness and educate the public on the spread of disease. The CDC later commented on this by saying "The game creates a compelling world that engages the public on serious public health topics".

Early in the game, before your infection gets noticed, there is a chance you will receive a message reading, "Pylons 'vital to high-tech society' A new energy report confirmed the need to construct additional pylons in order to ensure a sustainable energy supply in the future"

This is a reference to the Protoss race from Starcraft, who are required to build pylons before they can build more units.