Bela Lugosi was offered the role of the monster, but refused on the grounds that his character would not speak (though he eventually played the role in Frankenstein Meets the Wolf Man). Lugosi also insisted on creating his own makeup for the Monster, but his design was rejected. According to film historian Richard J. Anobile, Lugosi was originally offered the role of Dr. Frankenstein by original director Robert Florey, but Carl Laemmle insisted that Lugosi play the monster. Test footage of Lugosi in Monster make-up was filmed by Florey on the set of Dracula. Soon after, Florey was replaced by James Whale as director, and Lugosi was replaced by Karloff.

Edward Van Sloan (Dr Waldman) also makes an uncredited appearance as himself in the film's prologue, in order to warn audiences of what follows.

John Huston wrote an early version of the warning speech given at the start of the film.

John Carradine turned down the part of the Monster because he considered himself too highly trained to be reduced to playing monsters.

John Carradine, who later played Dracula in the Universal horror films, once claimed he was considered for the role of the Monster.

Carl Laemmle Jr. offered James Whale a list of 30+ film adaptations he could direct and Whale picked this one. Whale said he did so because he wanted to get away from the war pictures with which he had so far been associated. Ironically, Whale is now, by far, best-remembered for his four horror films.

Boris Karloff is considered a late bloomer in Hollywood. Frankenstein premiered when he was 44 years old.

Boris Karloff offered to remove his partial bridgework as part of the monster make-up process to create the sunken cheek look.

Boris Karloff's shoes weighed 13 pounds each.

Ken Strickfaden, who created all the electrical effects for the movie, also doubled for Boris Karloff during the sequences that showed the million volt sparks playing over his body. The same machines were later used in the comedy Young Frankenstein.

A 20-minute test reel, starring Bela Lugosi as the monster and directed by Robert Florey, was filmed on the Dracula sets. This footage has not been seen since 1931 and is now considered lost. Only a poster, featuring the vague likeness of Bela Lugosi as a 30 feet colossus, remains.

A microphone was placed in the coffin used in the funeral scene to amplify the sound of the grave dirt hitting the lid.

According to The People's Almanac, at one point the movie was to have included a line of dialogue giving the Monster the name, Adam. The Almanac indicates that an early print of this film may have indeed been released with just such a scene, but that it was cut when audiences began referring to the Monster by the name Frankenstein.

According to the TLC network program "Hunt for Amazing Treasures", a unique six-sheet poster for the original 1931 release, showing Karloff as The Monster menacing Mae Clarke, is worth at least $600,000 US and is possibly the most valuable movie poster in the world. The only known (original) copy is owned by a private collector.

Actor Edward Van Sloan, who played Dr. Waldman in the film, appeared in the now-lost test reel with Bela Lugosi as the Monster. In an interview conducted shortly before his death, Van Sloan remembered that Lugosi's makeup resembled The Golem, with a large broad wig and "a polished clay-like skin." Unfortunately, no footage of the test or any photographs of Lugosi in this makeup are known to exist.

After bringing the monster to life, Dr. Frankenstein uttered the famous line, "Now I know what it's like to BE God!" The movie was originally released with this line of dialogue, but when it was re-released in the late '30s, censors demanded it be removed on the grounds that it was blasphemy. A loud clap of thunder was substituted on the soundtrack. The dialogue was partially restored on the video release, but since no decent recording of the dialogue could be found, it still appears garbled and indistinct. The censored dialog was partially returned to the soundtrack in the initial "restored version" releases. Further restoration has now completely brought back this line of missing dialog. A clean recording of the missing dialog was reportedly found on a Vitaphone disc (similar to a large phonograph record). Modern audio technology had to be used to insert the dialog back into the film without any detectable change in the audio quality.

As the essential part of the "lake scene" was cut from the film in 1931, theater and later TV audiences were left to wonder how the girl, that was found in the lake actually met her death. Upon restoration of the scene , in the 1980s, on home video and later on Turner Classic Movies (TV), viewers can see what the angry townspeople didn't. Perhaps one might be sympathetic to the monster, in spite of the tragic loss of the child.

At the climax, the Monster carries Dr. Frankenstein up the mountain side and through the mill. At the insistence of James Whale, Boris Karloff actually carried Colin Clive in these shots, which were filmed for hours over several days. The 41-year-old Karloff had physical difficulties due to moving in the padding, the back brace that was part of the costume, make-up and 13 pound lifted boots. He badly injured his back during these scenes (and in his 2 subsequent times playing the Monster). Back problems continued to plague Karloff throughout the remainder of his life.

By the time the ending of the film was changed, allowing Henry Frankenstein to live, Colin Clive was no longer available for additional scenes. For the shot of Henry in long shot in the bedroom behind his father, he was played by another actor; tradition has long held that it was future cowboy star Robert Livingston filling in for him.

Child actress Marilyn Harris had done several takes of the drowning scene, none of which turned out quite right. Although wet and tired, she agreed to do one last take of the scene, the one that appears in the finished film, after director James Whale promised her anything she wanted if she would do so. She asked for a dozen hard-boiled eggs, her favorite snack. Whale gave her two dozen. The DVD commentary for the film suggests that Harris wasn't actually a good swimmer, quoting Harris as saying that she had only a couple of swimming lessons before filming and had never dived under water before.