In 2006, Guillermo del Toro originally pitched The Strain as a television series, but negotiations broke down when the Fox Broadcasting Company network president asked him to turn it into a comedy.

An agent suggested expanding the concept into a novel series instead, which led del Toro to co-write a trilogy of books with Chuck Hogan, released between 2009 and 2011, before it was later adapted back into a TV series.

Del Toro and Hogan collaborated on the first year of writing the novels on a simple handshake agreement, with no contract or publishing deal in place.

Del Toro and Hogan initially declined film and TV adaptation offers after the first book's success because they didn't want a screen version to influence how they wrote the remaining novels.

FX was chosen as the network for the adaptation because it wanted to follow the books closely and supported the idea of a close-ended series of three to five seasons, mirroring the three-novel structure.

John Hurt originally played Abraham Setrakian in the first version of the pilot, but he dropped out and the role was recast with David Bradley, requiring his scenes to be reshot.

Del Toro had previously wanted to cast Roy Dotrice as Setrakian, who had played the character in live-action advertisements for the first novel.

The character of Vasiliy Fet was originally conceived with del Toro's frequent collaborator Ron Perlman in mind, but the role ultimately went to Kevin Durand, who had worked with showrunner Carlton Cuse on Lost.

Lauren Lee Smith was originally cast as Kelly Goodweather but was later replaced by Natalie Brown.

Del Toro wanted Doug Jones for a major role, but scheduling conflicts forced him to decline; Jones later took on the smaller parts of an Ancient vampire and the Master's previous incarnation instead.

Sean Astin was cast as Jim Kent because del Toro and Cuse thought it would be amusing to have 'the most famous sidekick of all time' turn out to be a betrayer.

Twelve swords used in the series were custom-made by the Missoula, Montana-based bladesmith company Zombie Tools.

FX reportedly committed $500,000 specifically to creature creation for the series.

The score was composed by Ramin Djawadi, who had previously worked with del Toro on the 2013 film Pacific Rim.

The original marketing key art featured a worm, the vector of the vampiric virus, burrowing through a person's eye; FX replaced the artwork on several billboards after public complaints.