The Explosm team has been creating short videos based on Cyanide & Happiness for years before working on the full show. The Explosm YouTube channel had over 3.6 million subscribers and 490 million views before The Cyanide & Happiness Show started airing.^[3] Some of these short videos, such as "Junk Mail" and "Confession", have proven "overwhelmingly popular" among fans of the webcomic.^[4]

The Cyanide & Happiness Show was funded by the means of a Kickstarter campaign in early 2013, where it collected a total of $770,309. This was more than three times the initial goal and broke the record of most money ever funded for an animated series on Kickstarter.^[5][6] Among the "zany gift offerings" given to Kickstarter backers was an "all-expenses-paid trip to Dallas for a Banana Bar Crawl replete with a banana costume, scepter, and crown".^[7]

When the Explosm team sat down to plan the first season, they realized 50 percent of the writing for it was already done, with some ideas being over five years old. Many of the stories used in The Cyanide and Happiness Show resulted from the team trying to make each other laugh while in a bar. Due to Wilson living in Fort Collins, Colorado, numerous plane rides and Skype calls had taken place during this process. As the show began to take shape, the team drew out management positions for themselves. McElfatrick was put in charge of art, DenBleyker covered animation and Wilson managed sound design and voice acting, but as the project went on, these roles loosened up. They outsourced some animation production to studios in the U.S., India (Digitoonz), South Korea (BigStar Enterprise, Inc.), and more.^[8][4]

The creators originally attempted to negotiate a TV series deal with cable networks, but due to "concerns about artistic compromise",^[7] their efforts were fruitless. One of the creators wrote:

"We walked away from the first two [networks] due to rights and creative control issues. We thought that we could settle those issues in the third deal, but things didn’t quite work out as we hoped. We’re starting to realize that TV as an industry just isn’t compatible with what we want to do with our animation: deliver it conveniently to a global audience, something we’ve been doing all along with our comics these past eight years. That's just the nature of television versus the Internet, I suppose."

— Explosm^[9]

The first episode of The Cyanide and Happiness Show premiered in an Alamo Drafthouse Cinema in Richardson, Texas, on 12 November 2014.^[4] Episodes of the series were released on YouTube, but are also available for DRM-free, low-price download. These downloads were released shortly before the episodes were uploaded to YouTube. According to the creators, once bought, people are free to copy, edit and spread the material to their liking.^[10]

The second season of The Cyanide and Happiness Show, which started in December 2015, was made available through the Seeso streaming service rather than YouTube. NBCUniversal Cable senior vice president Parra Hadden noted that, shortly after it was announced that The Cyanide and Happiness Show would be hosted on Seeso, the website saw a very large surge in traffic.^[11] Seeso renewed the series for a third season later in 2016.^[12] Prior to the closure of Seeso in late 2017, The Cyanide & Happiness Show was also made available on the streaming service VRV.^[13] The series premiered on cable television in February 2020 on Syfy's late-night programming block TZGZ.^[14]

In some countries outside the United States, similar to its format on Syfy, the series is aired as a 22-minute TV series, conjoining two episodes into one.^{[citation needed]}

In June 2024, Explosm Entertainment was reported to be working on new content for Animation+, a streaming service backed by Streaming Ink Media in partnership with Samsung TV Plus.^[15]

This section needs expansion. You can help by adding to it. (January 2015)

Imad Kahn of The Daily Dot described Cyanide & Happiness videos as an "odd, but hilarious, mix of abrupt black humor that's overtly weird and doesn't pretend to be profound. It really does feel like a group of writers with free reign [sic] to animate whatever their twisted minds can think of."^[3]