Anthony Hopkins stated that one of his goals in playing Hannibal Lecter for a final time was to re-establish that he is an evil serial killer, as Hopkins believed Hannibal had come to be seen too much as a likable anti-hero by audiences.
(at around 28 mins) The establishing shot of the Baltimore State Hospital for the Criminally Insane was re-used from The Silence of the Lambs (1991), as the building was no longer available for filming.
(at around 34 mins) When Will Graham first encounters Hannibal Lecter in the asylum, it was originally written that Graham would show his fear of Lecter. However, Edward Norton pointed out that Graham was a seasoned and veteran agent who would never show his fear to Lecter. Director 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.
When asked to reprise his role of the film, Anthony Heald was not sure if he would 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 (2001), had Hopkins declined.
The costume designer ordered the Dolarhyde clothing from mail-order catalogs to reflect the character's loner personality, as though he would order clothes this way himself in order to avoid human contact as much as possible.
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 (1986) (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.
The musician that Hannibal sees playing badly, and later serves to his dinner guests, is meant to be Benjamin Raspail, whose head Clarice Starling finds in The Silence of the Lambs (1991). In that film, Hannibal tells Clarice that he did not kill Raspail, merely "tucked him away, much as I found him." This is not a discrepancy in the book. Hannibal admits to having killed Raspail. The head in the jar was another man named Klaus.
Director of photography Dante Spinotti also filmed the movie Manhunter (1986), which was the first adaptation of the novel "Red Dragon." Director Brett Ratner, who had previously worked with Spinotti on The Family Man (2000), so wanted him to shoot this movie that he delayed principal photography so that Spinotti could finish shooting Pinocchio (2002).
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 (1991). 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.
The trivia item below may give away important plot points.
During the scene where Will Graham (Edward Norton) realizes that Hannibal Lecter (Anthony Hopkins) is the killer he is looking for, Lecter stabs him with a knife, but Graham fends him off with an arrowhead. This may be a subtle reference to how Hannibal was exposed in the novel. One of his victims was found horribly mutilated with multiple stab wounds. Graham discovers that the victim has a scar from an old wound that was caused by an arrow, and finds out that Hannibal Lecter was the physician who had treated the wound. Graham visits Lecter a few times in the hope that Lecter may be able to provide a helpful lead. During one visit, he notices an illustration in one of Lecter's books, depicting a man with the exact same stab wounds as the victim, which makes him realize that Lecter himself is the killer. However, just as in the movie, Lecter surprises Graham and nearly stabs him to death.