Before the novel's publication, Orion Pictures partnered with Gene Hackman, who was set to direct and possibly star as either Jack Crawford or Hannibal Lecter, splitting the $500,000 rights cost with the studio.

Owing to the financial failure of Manhunter (1986), producer Dino De Laurentiis lent the rights to the Lecter character to Orion for free.

Gene Hackman withdrew from the project mid-development because his children wanted him to stop making violent films, but Orion co-founder Mike Medavoy encouraged screenwriter Ted Tally to keep writing while the studio secured financing and a new director.

Amblin Entertainment passed on the project because directing it was considered out of character for Steven Spielberg; Jonathan Demme signed on to direct after reading the novel, even before the screenplay was finished.

Jonathan Demme's first choice for Clarice Starling was Michelle Pfeiffer, who turned it down due to nervousness about the subject matter; Meg Ryan also declined for the same reason, and Molly Ringwald auditioned but was deemed too young.

Sean Connery was originally offered the role of Hannibal Lecter but turned it down; Anthony Hopkins was then approached based on his performance in The Elephant Man.

When Anthony Hopkins's agent mentioned a script titled The Silence of the Lambs, Hopkins initially joked, 'Is it a children's story?' but after reading the first 10 pages called it 'the best part I've ever read.'

Other actors considered for Hannibal Lecter included Al Pacino, Robert De Niro, Dustin Hoffman, Jeremy Irons, Derek Jacobi and Daniel Day-Lewis, and Forest Whitaker has said he auditioned for the part as well.

Anthony Hopkins drew inspiration for Lecter's voice and stillness from the HAL 9000 computer in 2001: A Space Odyssey and from writer Truman Capote's vocal patterns, though he denied basing it on Katharine Hepburn or Charles Manson as some had speculated.

To prepare for playing Jack Crawford, Scott Glenn was given a tour of Quantico by FBI profiler John E. Douglas, who also played him an audio recording of real serial killers torturing a victim; Glenn reportedly wept and even changed his stance on the death penalty afterward.

Anthony Hopkins's iconic restraint mask was created by Ed Cubberly of Frenchtown, New Jersey, who normally made masks for NHL goaltenders.

Filming took place mostly around Pittsburgh, Pennsylvania, with the Victorian house used for Buffalo Bill's home located in Perryopolis, and the exterior of the Baltimore State Hospital filmed at the Western Center near Canonsburg.

The FBI allowed rare on-location filming at the FBI Academy in Quantico, with some real FBI staff members appearing in bit parts.

A scene set in the FBI Director's office was actually filmed in the real office of U.S. Secretary of Labor Elizabeth Dole in Washington, D.C.

The design of Buffalo Bill's basement and pit was inspired by the real-life kidnappings and murders committed by Gary M. Heidnik.

Howard Shore's score was recorded in Munich in the summer of 1990, performed by the Munich Symphony Orchestra, with Shore aiming for music that blends invisibly into the film's overall sensory experience.

The song 'Goodbye Horses' by Q Lazzarus became a cult hit after being featured in the memorable scene of Buffalo Bill applying makeup in front of a mirror.

The Silence of the Lambs won the 'Big Five' Academy Awards (Picture, Director, Actor, Actress, Adapted Screenplay), becoming only the third film in history to do so, and remains the only horror film to win Best Picture.

The film's original poster was named the best film poster of the past 35 years at the 2006 Key Art Awards, and it was selected for preservation in the U.S. National Film Registry in 2011.

When re-released in the UK in 2017, the British Board of Film Classification reclassified the film from an 18 to a 15 certificate, with the co-producer suggesting audiences had become desensitized to its content.