Hell on Wheels was created by brothers Joe and Tony Gayton in late 2008 after they were inspired by an American Experience documentary about the transcontinental railroad, which revealed the corruption and greed behind the project's financing.

Co-creator Joe Gayton explained that the show focused on the Union Pacific side of the railroad rather than the Central Pacific due to budget and time constraints, which meant Chinese immigrant laborers were largely absent from the story until the fifth season.

In 2012, AMC announced that series creators Joe and Tony Gayton would no longer be involved in day-to-day production; John Shiban was initially set to take over as showrunner, but after his departure, writer John Wirth (previously of Terminator: The Sarah Connor Chronicles) became showrunner starting with season three.

Jake Weber was originally cast to play a carpetbagger character for season four, but his role was changed to John Allen Campbell, the first governor of Wyoming.

Actress MacKenzie Porter replaced Siobhan Williams in the recurring role of Naomi, Bohannon's Mormon bride, after Williams had portrayed the character as a guest star in season three.

Irish actress Dominique McElligott landed the role of Lily Bell almost by accident, having traveled to the US for free with flight attendant friends and auditioning for the part just days after arriving, never expecting to be cast in an American period role.

Christopher Heyerdahl, who played Norwegian character Thor 'The Swede' Gundersen, noted the rarity of playing a Scandinavian character on screen and said his own background and understanding of Norwegian culture made the role feel tailor-made for him.

Filming of season three was suspended partway through the sixth episode due to a mandatory evacuation caused by severe flooding in southern Alberta; star Anson Mount shared photos of the flooding sets and nearby river on social media.

The series was filmed largely around Calgary, Alberta, with season one shot mainly on the T'suu T'ina Native Indian Reservation, and season five using the CL Ranch west of Calgary along with the Kananaskis Country park system to stand in for the Sierra Nevada mountains.

The pilot episode drew 4.4 million viewers, making it AMC's second-highest series premiere ever at the time, behind only The Walking Dead, and the show maintained its status as AMC's second-highest rated original series through season one.