Director of photography Dante Spinotti also filmed the movie Manhunter, which was the first adaptation of the novel "Red Dragon". Director Brett Ratner, who had previously worked with Spinotti on The Family Man, so wanted him to shoot this movie that he delayed principal photography so that Spinotti could finish shooting Pinocchio.
Anthony Hopkins, Anthony Heald and Frankie Faison all reprise their roles from earlier films in the series. Faison is the only one of them to have appeared in all of the first four Thomas Harris "Hannibal" adaptations, having also appeared in Manhunter (albeit in a different role).
Although Anthony Hopkins was more than 10 years older than the first time he played this role, the film takes place before the first one. To help make him look younger some of his wrinkles and crow's feet were removed digitally for the close-ups, and he had to lose an substantial amount of weight.
When asked to reprise his role of the film, Anthony Heald wasn't sure if he'd be able to. Tim Roth became a candidate for a younger Dr. Chilton and negotiations began. At the last second, Heald became available. Interestingly enough, Roth was also considered as a possible replacement for Anthony Hopkins in Hannibal, had Hopkins declined.
Screenwriter Ted Tally was unaware that Frankie Faison would reprise his role of Barney, and indicated that he would have elaborated on Faison's role if he had known.
After finding out that Dolarhyde knows where he lives, Will brings his family to a horse and sheep ranch, a reference to the story of Clarice's childhood in The Silence of the Lambs.
In William Blake's "Great Red Dragon" series of paintings, there are two with very similar names. The novel "Red Dragon," by Thomas Harris, uses the title of one painting ("The Great Red Dragon and the Woman Clothed with the Sun"), but in describing the image, gives a description of another ("The Great Red Dragon and the Woman Clothed in the Sun"). Due to the muddled reference, the first adaptation of the the novel, Manhunter (dir: Michael Mann), Francis Dolarhyde is obsessed with the painting that Harris cites by name, while this film features the painting as described by Harris, which is a back view of the dragon with his tail wrapped around the woman.
In the scene where Will Graham first encounters Hannibal Lecter following his capture of Lecter, it was originally written that Graham would show his fear of Lecter. However, Edward Norton pointed out that his character, Graham, was a seasoned and veteran agent who would never show his fear to Lecter. Brett Ratner then suggested that Graham would be afraid, but wouldn't show it, and they came up with the idea of Graham having massive armpit sweat stains following his encounter with Lecter.
During filming, Michael Jackson made a surprise visit to the set. He and director Brett Ratner have known each other since Ratner's music video career.
With the exception of the pre-title prologue, all three returning cast members (Anthony Hopkins, Anthony Heald and Frankie Faison) are seen only in the confines of the hospital.
The BTK Killer, in which the Dolarhyde character is based on, was captured in 2005 and sentenced to 10 consecutive life sentences spanning until no earlier than 2080.
The novel 'Red Dragon' by Thomas Harris was first published in 1981, ten years before Anthony Hopkins was cast as Hannibal Lecter in The Silence of the Lambs. Nevertheless, it would seem that Welshman Hopkins was destined to play Lecter as the emblem on the flag of Wales is of a large red dragon on a green and white field. In the Welsh language, the flag's name is "Y Ddraig Goch," meaning literally The Red Dragon.
Edward Norton is the only actor who appears with two other actors who played the famous role of Lecter - Brian Cox and Anthony Hopkins. Norton would later appear with Cox in 25th Hour.
At the end of Hannibal Lecter's note in the Tattler to the Tooth Fairy, it says "Bless you, 666." 666 is the mark of the Beast in the Book of Revelation.