The game uses an epidemic model with a complex and realistic set of variables to simulate the spread and severity of the plague.

Plague Inc gives you the Fake News, Ultimate Boardgames, Science Denial, Mad Cow Disease, and The Black Death scenarios for free.

Development most likely started in 2011 with the British creator, James Vaughan, working on the game in his afternoons and evenings.

In July 2014, Ndemic Creations partnered with 20th Century Fox on an update themed as a tie-in to the film Dawn of the Planet of the Apes.

Players cultivate the film's "Simian Flu" virus, which kills humans while making apes more intelligent.

[15] On 6 December 2018, Ndemic Creations released Rebel Inc., a follow-up game with a political theme based around the "complexities and consequences of foreign intervention and counter insurgency.

[20] On 28 February 2019, the studio announced that they would add an in-game scenario about vaccine hesitancy to the game, after a Change.org petition to do so gained over 10,000 signatures.

[21] On 24 March 2020, the studio announced that they would add a "cure mode" about stopping the plague outbreak due to the ongoing COVID-19 pandemic.

[24] Originally released on the mobile version only, the game mode was later brought to Evolved on PC via a downloadable content update on 28 January 2021.

[28] Wired.com cited Plague Inc. as a notable independent developer success story as it "bucked the system by staying near the top of the charts in numerous countries for the entirety of its existence, pulling in millions in revenue while competing with the big players".

[39][40] In the wake of the COVID-19 pandemic in January 2020, Plague, Inc. became the top-selling app in the Chinese market, and saw increased sales and number of concurrent players on other platforms.

The interest was believed to be from Chinese video gamers trying to find a way to deal with fears raised by the outbreak.

Ndemic reminded players that while Plague Inc. was developed based on scientific understanding of the spread of infectious diseases, the game was not on par with any scientific model, and added links to the World Health Organization's website on their own website in response to people inquiring about the coronavirus.

[51] Dark Realm Studios initially complained on Twitter to IGN reviewer Justin Davis about the Plague Inc. release, saying that the game was "just an attempt to cash in on Pandemic 2.5" due to similarities in gameplay between the titles.

Following the talk, the CDC said that it was interested in Plague Inc. as "it uses a non-traditional route to raise public awareness on epidemiology, disease transmission, and diseases/pandemic information.

[56] The game itself got updated with more realistic situations following the CDC meeting as Vaughan got scientific tips regarding pathogens and transmission.