While the V.A.T.S. targeting system is an evolution of the targeted shot mechanic in earlier Fallout games, the slow-motion visuals were inspired by the Crash Mode Replays from the Burnout series. Artist Grant Struthers prototyped the V.A.T.S. camera system by filming stop-motion fight scenes with his Incredibles action figures.

The drug "Med-X" was originally just called Morphine, but in order to get a MA15+ rating in Australia by the Office of Film and Literature Classification (OFLC) board, all references to Morphine had to be changed to "Med-X". During the time there was no higher age rating (R18+) for video games, which would have meant the game could not be sold in Australia. The reason the OFLC board didn't pass the game was because of the usage of real-life drugs.

The voice of the protagonist as a baby is actually Game Director Todd Howard's son, Jake Howard.

When creating the gun-system for Fallout 3, one of teams first tests was taking a bow from Oblivion and making a Bow and Arrow "gun." It shot rapid-fire arrows and apparently "didn't work quite right", so the new gun-system for the game was built up from scratch.

The 2008 E3 trailer for the game contains a Vault-Tec commercial which advertises a phone number. Calling the 1-888-4VAULT-TEC number will play an automated message saying:

When talking to Milo, the shipping foreman of the Nuka-Cola Plant, asking for the shipping manifest and will result in him giving the player the terminal pass-code, NC-C1864. This is the registry number for the USS Reliant in the movie "Star Trek: The Wrath of Kahn".

The Super-Duper Mart and the first Wasteland Survival Guide quest that accompanies it were likely thought up after an electrical storm knocked power out for 8-10+ hours in the Bethesda studio. Todd Howard and several other staff members went to a local Supermarket, using an iPhone to light their way across the pitch-dark aisles and essentially began to brainstorm ideas from that experience.

A cafeteria bulletin board found in Vault 101 shows an advertisement for a Bingo Night, with the first prize being "a week's supply of Water Rations."
The "13" bingo-ball on the advertisement strongly suggests a call-back to the original Fallout, which starts out with Vault 13's Water Chip failing and requiring the Vault Dweller to go out and search for a new one.

The village of Arefu is an actual real-world place inside of Romania, most well known for its proximity to the former castle of Vlad III, who is also known as "Dracula" and "Vlad the Impaler." It is also the main stage for the questline "Blood Ties", which deals with a group of cannibals who believe themselves to be vampires. One of the NPCs involved with the questline, Lucy West, is likely based off of Lucy Westenra, a character from Bram Stoker's Dracula.

The group of vampires call themselves, "The Family", are likely a reference to the 1971 Charlton Heston film The Omega Man, featuring a nocturnal breed of pale, vampyric mutants that live underground, referring to themselves as "The Family." Lastly, the password to open a locked-door containing one of the quest-line NPCs is "Vespertilio," which is a genus of the bat family.

In Megaton, the undetonated atomic bomb and the Children of Atom are a reference to the film "Beneath the Planet of the Apes", in which a cult worships an intact nuclear ICBM.

The inhabitants of the Temple of the Union are named after Abraham Lincoln's cabinet;
Hannibal Hamlin was Vice President, Caleb Smith was Secretary of the Interior, William "Bill" Seward was Secretary of State, and Simon(e) Cameron was Secretary of War. On top of this, the dog found there is named "Four Score", which is a reference to Abraham Lincoln's opening of the Gettysburg Address ("Four score and seven years ago...").

A modified Mister Gutsy, named "Sawbones", can be found at the Citadel. When first encountered, it greets the player with the phrase "Please state the nature of the medical emergency." This is a reference to the EMH Mk 1 program (aka The Doctor) from Star Trek: Voyager. In addition to the phrase, it also shares a similar personality to The Doctor which includes the bad bedside manners, as well as an interest in arts (in Sawbone's case, writing poetry) which separates it from normal Mister Gutsys, much like how The Doctor stood out among his EMH counterparts.

Several references to horror stories and movies can be found in the game. In the Point Lookout DLC, a unique knife called the "Toy Knife" can be found alongside a Hockey Mask, referencing Jason Voorhees from the movie series Friday the 13th.

Another reference is found in both the standalone Fallout 3 and in Point Lookout, the first being in a simulation called Tranquility Lane, in which the player can don a clown mask as a kid and begin a killing-spree within the simulation. The second time the mask pops up is in Point Lookout, which is found on top of a skeleton in a bathtub inside a motel room, which itself is adorned with skeletons and blood splattering. This is a reference to Michael Myers from the Halloween movie series, and more specifically his first kill where he wore a clown suit and mask, doing so as a kid.

H.P. Lovecraft references appears in the standalone Fallout 3 too, with the inclusion of the Dunwich Building. The story told through the building via Audio Logs and the apparent obelisk near the end references the Cthulhu Mythos, more specifically the story called The Dunwich Horror, which the very building is named after. The player can also hear the word "Alhazred" from the Obelisk alongside one of the last audio logs, which refers to the fictional author of the Necronomicon, who is named Alhazred. The narrative is extended even further with the inclusion of the Point Lookout DLC, which includes an actual quest line involving a tome named The Krivbeknih and the owner of the book, Obadiah Blackhall. The Krivbeknih is in reference to the number of various books/tomes and artifacts featured predominately in Lovecraftian stories, and the Blackhall family is another reference to The Dunwich Horror, namely that of the Wheatley Family, as well as a possible reference to the central family in The Lurker at the Threshold, which involves an aristocratic man that inherits his family's dark legacies.

The arts-centered Vault 92 holds a number of musical and sound-related references;
• The Overseer of Vault 92 is named "Richard Rubin", who is likely named after music producer Rick Rubin.
• "Zoe Hammerstein" gets her name from Broadway lyricist and songwriter Oscar Hammerstein II, who helped make the song "I'm in Love with a Wonderful Guy", which is played in-game on the GNR Radio Station.
• "Gordon Sumner" is actually the real name of the musician known as Sting.
• "Professor John Malleus" is named after the one of the three auditory ossicles, (small bones located in the middle ear) which transmit sounds from the air to the inner ear. The Malleus is the "hammer" in the set of "hammer, anvil, and stirrup," so named after their shapes.

The mutant fire-ant centered quest called "Those!" is a reference to the 1954 film titled "Them!", in which ants are mutated by atomic tests in New Mexico, which in turn makes them gigantic and wreck havoc upon civilization.

The scenario at the beginning of the game where Butch steals the player's sweetroll is a reference to a running gag in The Elder Scrolls series, where the game asks what the player would do when someone tries to take their sweetroll.

Originally Liberty Prime was planned to be massive and would allow players to ride inside his head during the final mission, but this idea was scrapped before the game's release.

According to Emil Pagliarulo, the lead designer for Fallout 3, Tranquility Lane's Betty was inspired by the character Billy Mumy from the Twilight Zone episode "It's a Good Life." In the episode, Billy, a "little kid with godlike powers terrorizes the inhabitants of a town, and 'wishes' them into the cornfield when they're bad."

Dogmeat is an Australian cattle dog, and was modelled after the dog from Mad Max 2. He is also named after the dog from "A Boy and His Dog", a 1975 post-apocalyptic movie.

In "The Pitt" DLC the player can collect 100 steel ingots and return them to a man named Everett. After turning in all 100 Everett says "Yup, guess you got every last one out there. You're one hell of a steeler, kid." The name 'steeler' is a common nickname for steel workers, but is also a reference to the NFL team, the Pittsburgh Steelers.