Due to a poorly received test screening, David Ellison, a financier at Paramount, became concerned that the film was "too intellectual" and "too complicated," and demanded changes to make it appeal to a wider audience, including making Portman's character more sympathetic and changing the ending. Producer Scott Rudin sided with Garland in his desire to not alter the film, defending the film and refusing to take notes. Rudin had final cut.

Oscar Isaac filmed this movie and Star Wars: The Last Jedi (2017) on adjacent studio lots. He had the same trailer for both films and would often film scenes for both movies on the same day.

Director Alex Garland decided not to reread the novel "Annihilation." Instead, he decided to adapt it "like a dream of the book."

On December 7, 2017, it was announced that due to the clashes between producer Scott Rudin and David Ellison, a financier at Paramount, and the shift in Paramount's leadership, a deal was struck with Netflix handling international distribution rather than releasing the film in theaters. According to this deal, Paramount would handle the U.S. and China release, while Netflix would begin streaming the film in other territories seventeen days later.

This film was based on the first book in the "Southern Reach" trilogy.

Although the story is often said to be inspired by Tarkovsky's film Stalker (1979), in a Reddit AMA writer Jeff VanderMeer denied any inspiration from the film nor from the novel (Roadside Picnic) that it was based on.

Prior to its release, the film drew some criticism for the casting of Natalie Portman and Jennifer Jason Leigh as characters who are, in the books, described as Asian and half-Native American. Garland explained that none of the five female characters' ethnicity is revealed in the first book, which is the only one of the trilogy he has read, and that the script was actually complete before the second book was published. He cast the characters based on his reaction only to the actors he met in the casting process, or actors he had worked with before. Because he wanted to take the story in his own direction, he did not read the other two books while making the film in order to not be influenced by them.

The first base the crew encounters within the shimmer is named "The Southern Reach." The movie is based on the Southern Reach Trilogy.

Frances McDormand was considered for the role of Dr. Ventress before Jennifer Jason Leigh was cast.

Anya tells Lena when they first meet at the Southern Reach that "The people here put themselves to sleep in fetal positions." Earlier, when Lena wakes up for the first time at the Southern Reach after getting sedated, she is seen stirring from a fetal position.

Oscar Issac and Sonoya Mizuno previously starred together in Ex Machina (2014), which was also written and directed by Alex Garland.

This was the first R-rated film between Paramount Pictures and Skydance, and the second Skydance film overall to receive that rating.

Julianne Moore and Tilda Swinton were in talks to star in the movie.

One filming location was Holkham Beach, Norfolk in the U.K., during July 2016.

Natalie Portman had stated earlier in her career that she'd never be in a horror movie. She changed her mind to appear in Black Swan (2010) and this film as she really wanted to work with the filmmakers. Scheduling conflicts prevented her from appearing in Pride and Prejudice and Zombies (2016), which she auditioned for and won.

Principal photography was underway by April 2016 when actor David Gyasi was added to the cast. Location filming by Lighthouse Pictures Ltd. occurred starting in late April in South Forest, Windsor Great Park. Some test shooting had already been done in St. Marks, Florida, but the vegetation in the area turned out to be too dense to give any perception of depth on screen. Lighthouse Pictures have a charge arrangement registered with U.K. Companies House regarding this matter. On May 9, 2016, cinematographer Rob Hardy began sharing pictures from the set of the film. On July 13 and 14, filming took place at Holkham Pines in North Norfolk. Shooting was completed that month.

The abandoned house they camp at within the Shimmer is architecturally identical to the suburban house Lena and her husband live in outside the Shimmer. Another example of the "echoes".

The snake tattoo that appears on Lena's wrist is not there before she enters the Shimmer. It also appears on the body of the soldier killed on the wall in the building they enter. The tattoo is a symbol of a snake eating itself, which ties into the film's theme of self-destruction.

The character names in this film, "Ventress," "Thorensen," "Radek" and "Sheppard," are identical to those in the novel "The Crystal World" by J.G. Ballard. In the novel, a physician takes a journey through Africa. Notably, it is described that the forest and its inhabitants start to crystalize. At the end of the film, the lighthouse is surrounded by crystal trees

In an interview with ew.com, Annihilation (2018) visual effects supervisor Andrew Whitehurst said they gave the horrific mutated bear creature from the movie a name. Whitehurst served as VFX supervisor at visual effects house Double Negative when the company worked on the movie Paddington (2014), which is about a talking bear. Whitehurst said Paddington is a very nice bear named after Paddington Station in London, which is a very elegant Victorian station, so they named the mutant bear in this film "Homerton," which is a slightly rough-around-the-edges station in East London.

The line that Ventress speaks in the tunnel where the meteorite struck ('Unfathomable mind. Now beacon. Now sea') is from Samuel Beckett's novel 'Molloy', itself the first part of a 'Trilogy', with 'Malone Dies' and 'The Unnamable'. In 'Molloy', the the title character is tracked down by a character called 'Moran'. Their identities appear to merge toward the end of the novel, which ties in with the theme of the double in 'Annihilation'.

The dance between Lena and her alien double was choreographed by Bobbi Jene Smith, an American choreographer and dancer. Smith was the subject of a documentary directed by Elvira Lind, the partner of actor Oscar Isaac.

The figure "8" tattoo in the movie is shaped like the symbol used for infinity in mathematics and depicts a snake/serpent eating its own tail (self-destruction) and is known as "Ouroboros".

Several characters, who directly interact with the shimmer, have doubles that can be identified by the 'Ouroboros' tattoo on their arm. In 2011, a group of French scientists identified a mutation in the brown Algae, 'Ectocarpus'. This organism has a two-stage life-cycle, with each phase producing a different form of the organism at a genetic level. The French scientists identified a mutation, which they called 'Ouroboros', that allows the sporophyte phase to mimic the gametophyte phase. In effect, this causes the organism to exist as a continuous gametophyte phase. This is similar to other, homeotic, mutations that cause specific organs to mutate into different organs, such as antennae in fruit flies converting to become legs. However, the Ouroboros mutation affects the whole organism and not just a single organ. See Coelho, S; Godfroy, O; Arun, A; Le Corguillé, G; Peters, A & Cock, J. M. (2011) OUROBOROS is a master regulator of the gametophyte to sporophyte life cycle transition in the brown alga Ectocarpus, PNAS 108(28): pp. 11518-11523 doi:10.1073/pnas.1102274108 This process is similar to the 'refraction' identified by the scientists in the Shimmer. The work falls within the scientific area of the genetic regulation of life cycle transmission, which is mentioned as Lena's specialism as a biologist.