During the post-production process of the film, Paramount kept Stan Winston's Kothoga creature under wraps much like Universal had done with Jurassic Park (1993), with no one permitted to talk about the production or the creature itself.

Because the novel portrayed the museum's administration in an unflattering light, they turned the film's producers down. Paramount Pictures offered the museum a seven-figure sum of money to film there, but the administration was worried that the monster movie would scare kids away from the museum. The producers were faced with a problem as only museums in Chicago and Washington, D.C., resembled the one in New York. The Field Museum of Natural History in Chicago loved the premise and allowed them to shoot there.

Penelope Ann Miller had not done a horror film prior to The Relic but was drawn to director Peter Hyams' desire to have a strong, smart female lead. Tom Sizemore was attracted to the film because he got to play the male lead: "I had the responsibility of pushing the narrative forward."

Harrison Ford was director Peter Hyams's first choice for the lead role of Vincent D'Agosta (played by Tom Sizemore).

The character of D'agosta is actually a melding of two characters from the book. The characters combined are D'agosta and FBI agent Pendergast which is the main character in the sequel book and many books after.

The preparation of the fictional elixir given to John Whitney by the Amazon tribesmen, and the ceremony surrounding it, strongly parallels the real-life consumption of ayahuasca, a psychoactive tea used religiously by numerous Amazon tribes.

The giant monster-head gate through which the Superstition exhibit is entered is an actual-size replica of the Orcus gate at Parco del Mostri (Park of the Monsters) in Bomarzo, Italy. Carved over the entrance are the words "lasciate ogni speranza voi ch'entrate" (abandon all hope, all ye who enter here). According to the Divine Comedy, by Dante Alighieri, these are the words carved on the entrance to Hell.

Makeup artist Stan Winston and his team made three creatures with two people moving the heads and people on the side working the electronics to move the arms, claws, mouth, and so on. Hyams reviewed Winston's early drawings and his only suggestion was to make the monster more hideous looking. The director also suggested certain invertebrates for inspiration and Winston came up with an arachnoid outline for the monster's face. In the scenes where the creature is running or jumping, a computer-generated version was used.

The improvised explosive Margo makes using two jars is very similar to the one made by Jean-Claude Van Damme's character in Sudden Death (1995), director Peter Hyams' previous film.

When Peter Hyams was hired to direct he stated "I don't think you can scare people, unless you involve them because a movie like this has to be intelligent."

The two sniffer dogs used to track down the creature in the sewer system are named "Castor" and "Pollux" after the Dioscuri from Roman/Greek mythology.

Audra Lindley (Dr. Zwiezic) and James Whitmore (Dr. Frock) had been married at one time and at the time of their appearances in this film, in which they shared no screen time, they had been divorced for 18 years.

The film was originally set to open in August 1996 but special effects work delayed its release till the end of the year/early 1997.

In addition to shooting on location in Chicago, a set was built in Los Angeles of a tunnel flooded with water.Tom Sizemore spent most of the shoot either damp, cold or soaking wet and, as a result, caught the flu twice. The production was shut down briefly when Peter Hyams became too sick to work

Audra Lindley's last feature film.

The Kothoga has about 4 minutes of screentime.

David Seltzer's name was attached to the initial promos for the movie. For an unknown reason, it had been removed by the time the film went into general release.

The book takes place in the New York Museum of Natural History.

The disappearance of the Blaisedales explained: When the Kothoga attacks the 5 people left behind in the museum after the blackout, the Blaisedales embrace each other and scream. Then the screen shot changes a couple times, and that's the last you see of them. In the original cut, the Blaisedales run through the lab, and are attacked by the Kothoga. They are then partially consumed by the bone stripping museum beetles.

When Margo is later chased through all the closed doors by the Kothoga, she falls over them and screams when she sees their bloody corpses. This scene was most likely cut out of the film because it was deemed too gruesome for audiences.

One of a number of space / science fiction / fantasy films of writer-director Peter Hyams. The sci-fi / fantasy movies are: Outland (1981), Timecop (1994), Capricorn One (1977), End of Days (1999), Stay Tuned (1992), 2010: The Year We Make Contact (1984), and The Relic (1997).

Linda Hunt and Penelope Ann Miller also starred together in Kindergarten Cop.

Penelope Ann Miller, Linda Hunt, and Chi Muoi Lo all starred previously in the movie, Kindergarten Cop.

Jophery C. Brown was also killed by a large creature four years earlier in Jurassic Park (1993).

John DiSanti's last film (or TV) role to date (2018).

The Kothoga has 5 minutes of screentime.

Second film in which Penelope Ann Miller plays a character named Margo. She played Margo Lane in her previous film The Shadow (1994).

Peter Hyams: [Spota] a character named Spota.

In the book the chracters of Dr. Frock and Dr. Lee don't die and are actually major chracters in the sequel called "The Reliquary".

The appearance of the Kothoga creature was purposely left till the last half of the film because Stan Winston's creature was not completed in time for the scenes requiring the visual and physical presence of it on set. It was also one of the reasons the film was delayed until the winter of 1996/97.

In the storage area Lieutenant D'Agosta says "not the good place to light a match" foreshadows the ending when Margo Green creates a double jar chemical explosive in the storage area to destroy the Kothoga.

To destroy the Kothalga creature, Dr. Green (Penelope Ann Miller) makes a double-jar chemical bomb. In Sudden Death (1995), Darren McCord (Jean-Claude Van Damme) makes the same type of bomb in order to break into VIP box at the Stanley Cup finals. Both films were directed by Peter Hyams.