It is a science fiction mystery drama with a time traveling plot loosely adapting the 1995 film of the same name, which was written by David and Janet Peoples and directed by Terry Gilliam, itself being inspired by Chris Marker's 1962 featurette La Jetée; the series credits Marker and both Peoples for their original works.

In the series, Aaron Stanford and Amanda Schull star as James Cole and Dr. Cassandra "Cassie" Railly, two strangers were brought together by destiny on a mission to use time travel to stop the destructive plans of the enigmatic organization "Army of the 12 Monkeys".

Stanford, Schull, and Hampshire play reimagined versions of characters respectively portrayed by Bruce Willis, Madeleine Stowe, and Brad Pitt in the 1995 film.

In the year 2043, scavenger James Cole (Aaron Stanford) has been recruited by a team of "Project Splinter" scientists led by physicist Katarina Jones (Barbara Sukowa), to travel back in time to the year 2015 and stop the release of a deadly virus by the enigmatic organization known as the "Army of the 12 Monkeys".

Cole will also encounter a seemingly unstable math genius named Jennifer Goines (Emily Hampshire), whose father Cole has been ordered to kill, Cassie's ex-boyfriend Aaron Marker (Noah Bean) and the dangerous high-ranking members of the Army of the 12 Monkeys, "Pallid Man" (Tom Noonan) and Olivia (Alisen Down).

Cole and Cassie will try to unveil the identity and whereabouts of the mysterious leader of the Army of the 12 Monkeys, who is only known as "the Witness" and who is always one step ahead of them.

Terry Matalas and Travis Fickett, who had written together for the series Nikita and Terra Nova, wrote an original spec script television pilot with a time travelling plot, named Splinter.

[17] Eventually, the script found its way to Atlas Entertainment's offices, who had produced the 12 Monkeys movie and had been wanting to create a TV series based on it for some time.

[21] "Ultimately, our version of predestination – and where it diverges from La Jetée or the original film – is that it's a basically a bullfight, a ballet, against Time.

The idea of a closed loop works beautifully in a film, but for the story and the emotion of a TV series to really resonate, the characters and the audience have to believe that change is possible.

On July 22, 2013, The Hollywood Reporter first revealed that Syfy was developing a 12 Monkeys television adaptation, in the form of a 90-minute backdoor pilot that would lead to a straight-to-series order, similarly to what the Battlestar Galactica miniseries did.

[23] The following month, it was reported that Syfy decided to green-light an hour-long pilot, which would be executive produced by Roven and Suckle, with production set to begin in November.

[19] Matalas presented the series as a "complete reimagining" of the film and not just a remake, citing Looper as an inspiration for the time travel visual effects.

[28] Madeleine Stowe, who played the equivalent of Amanda Schull's character in the film, narrated the opening of the season 2 premiere and made an appearance in its finale.

[29] Two major differences compared to the movie are that this version of time travel allows for changes in the past to affect the future, and that the "Army of the 12 Monkeys" is a real organization rather than a red herring.

[40] Fickett left his position as executive producer and was credited as consultant, leaving Matalas the sole showrunner for the season.

[44][45] Starting with the second episode, the bulk of principal photography for the series took place in Toronto, both on location and at the Cinespace Film Studios,[46][47][48] where they constructed sets like the room with the time machine.

[54][55] Standing sets used in the series were changed constantly to reflect both older and newer versions of the locales and also alterations to the locations that resulted from the characters' trips through time.

To get more shooting days out of the production's schedule, two camera units shot in parallel resulting in episodes featuring work done by both Greene and Mojsovski.

Greene decided to ignore the visual style of the original film, as he felt the series told a different story than it had.

[58] Instead, Greene's biggest stylistic influence while establishing the show's look in the first season was the film Children of Men, which he referenced for the look of the future timeline.

[65] The original film's theme music – an arrangement of Astor Piazzolla's Suite Punta del Este made by Paul Buckmaster – can be heard during the ninth episode of the second season, "Hyena".

[82] In Australia, Via Vision released a limited edition on Blu-ray on August 19, 2020, that collects the four seasons, the original film, a bonus disc, and a foldout map of "The Word of the Witness", an item that features prominently in the story.

The website's critical consensus reads, "The nonsensical time travel in 12 Monkeys makes it less watchable than its original source material, but the high quality execution and cool characters are top-notch.

[92] Christine Seghers rated the first season 8.8/10 and wrote in her review for IGN: "What started as a simple 'let's go back and fix this' story soon blossomed into a deep philosophical mediation on the concept of predestination versus free will.

The assigned critical consensus reads: "Full of addictive twists, the second season of 12 Monkeys overcomes time traveling logic issues with help of added thriller elements.

The critical consensus of the website reads: "12 Monkeys continues to raise the bar with each marvelously complex episode in a knock-out fourth season that proves as unpredictable as it is gratifying.

"[105] Before the 12 Monkeys series premiere, Terry Gilliam, director of the original film, expressed his reservations about the concept: "It doesn't have anything to do with me and no-one has contacted me.

"[107] However, according to Matalas, both the Peoples and Marker read the pilot and gave the series creators their blessing and support to move forward with it.

[109] Madeleine Stowe, lead actress of the original film, became supportive of the filmmakers after watching the pilot, appreciating the differences between her character and Amanda Schull's interpretation.