Terry Matalas and Travis Fickett originally wrote an unrelated spec pilot called 'Splinter' about time travel, which Atlas Entertainment later helped transform into a 12 Monkeys adaptation.

From the original 'Splinter' script, only a few elements survived into the final show: the overall plot structure of stopping a man from doing something in the past, the recurring watch appearing across time periods, the term 'splintering' for time travel, and the female lead's name 'Cassie'.

The series was originally pitched to Syfy as a 90-minute backdoor pilot meant to lead to a straight-to-series order, similar to how the Battlestar Galactica miniseries worked.

Production of the pilot was held up because the show was labeled 'cast contingent,' meaning filming could not begin until the roles of Cole and Goines were cast.

Madeleine Stowe, who played the film equivalent of Amanda Schull's character, narrated the opening of the season 2 premiere and later appeared in a small but pivotal guest role that season after being won over by the pilot's take on her original character.

Terry Gilliam, director of the original 1995 film, publicly criticized the series concept before it premiered, calling it 'a very dumb idea' and noting no one had contacted him about it.

According to Matalas, both David and Janet Peoples (screenwriters of the film) and Chris Marker (creator of La Jetée) read the pilot script and gave their blessing for the series to move forward, despite Gilliam's public skepticism.

The pilot was filmed in Detroit, but from the second episode onward, the bulk of the series was shot in Toronto, including at Cinespace Film Studios where the time machine room set was built.

For location work, the Republic of North Macedonia stood in for Chechnya and the Dominican Republic doubled for Haiti in the first season, while later seasons filmed in Budapest and Prague to take advantage of older European architecture for 1950s settings.

Cinematographer David Greene said his biggest stylistic influence for the show's bleak future timeline was the film Children of Men, and he deliberately ignored the visual style of the original 12 Monkeys movie since he felt the series told a different story.

Visual effects were handled by Stargate Studios for season 1 and then by Folks VFX from season 2 onward, with an average of 60–75 effects shots per episode, ranging up to 100–125 in some episodes.

An arrangement of Astor Piazzolla's Suite Punta del Este, the original film's theme music, can be heard during the second season episode 'Hyena' as a tribute to the movie.

The show's critical reception improved dramatically over time: while season 1 got mixed reviews (60% on Rotten Tomatoes), later seasons scored much higher, with season 3 and season 4 both reaching 100% approval ratings on the site.