The film is based on the first volume of Max Allan Collins and Richard Piers Rayner's graphic novel, which was brought to Steven Spielberg's attention through the Zanuck family before Spielberg set the project up at DreamWorks.

Sam Mendes took on the project after American Beauty, having also considered directing A Beautiful Mind, K-PAX, The Shipping News, and The Lookout instead.

The story is deeply informed by the manga series Lone Wolf and Cub, with Max Allan Collins acknowledging in a BBC interview that his graphic novel was 'an unabashed homage' to it.

Early drafts of the screenplay depicted Michael Sullivan as an alcoholic, but this element was removed from the final version, and some character surnames were changed from the graphic novel, such as O'Sullivan being shortened to Sullivan and Looney becoming Rooney.

Author Max Allan Collins wanted to write the screenplay himself but was not given the chance, instead serving only as a consultant; he later disagreed with several changes, including the added profanity, the altered fate of the son's actions, and the shift in narration from an adult priest to a young boy.

Tom Hanks first received the graphic novel from Steven Spielberg while filming Cast Away, but only became attached after later reading David Self's screenplay adaptation.

Tyler Hoechlin was cast as Michael Sullivan Jr. from over 2,000 candidates and, at age 13, was trained by a driving instructor to perform the getaway-driver scenes.

Paul Newman was the unanimous first choice to play John Rooney, and he prepared for the role by having Angela's Ashes author Frank McCourt record a tape of his voice to study his Irish-American cadence.

To achieve Harlen Maguire's seedy look, Jude Law was given a sallow, darkroom-worn skin tone, a lower gumline with rotted-looking teeth, and a thinning hairline.

Anthony LaPaglia filmed a single scene as Al Capone that was ultimately cut from the film and only appears among the DVD's deleted scenes, since Mendes felt Capone was more menacing as an unseen presence; Alfred Molina had earlier been approached for the role but turned it down due to scheduling conflicts with Frida.

The film was shot on location around Chicago, including the University Club of Chicago, the Pullman neighborhood, the Charles G. Dawes House in Evanston, and Geneva, Illinois, with interior sets for the Sullivan and Rooney homes built inside the General Jones Armory.

Exterior scenes were filmed during the actual winter and spring of 2001 in Illinois, using real snow, rain, and mud to reflect the characters' emotional states, with filming concluding in June 2001.

A seamless 40-second driving scene showing Michael Sullivan and his son heading into Chicago was filmed on LaSalle Street, with visual effects used to add the Balbo Drive skyline background where the real street lacked scenery.

Conrad L. Hall won the Academy Award for Best Cinematography posthumously for his work on the film.

In April 2006, Empire magazine ranked Road to Perdition No. 6 on its list of the top 20 comic book films.

Max Allan Collins was hired to write the film's novelization but had to cut his 90,000-word draft down to 50,000 words per DreamWorks' licensing restrictions; his original longer version was later published in 2016 as Road to Perdition: The New, Expanded Edition.