Production notes

The film was the original idea of Otto Klement and Jerome Bixby. They sold it to Fox, which announced the film would be "the most expensive science-fiction film ever made". Richard Fleischer was assigned to direct and Saul David to produce; both men had worked at the studio before. Fleischer had originally studied medicine and human anatomy in college before choosing to be a film director. Harry Kleiner was brought in to work on the script. The budget was set at $5 million. The budget went up to $6 million, $3 million of which went on the sets, and $1 million on test footage. The Proteus submarine was constructed as a full-size set piece 42 feet long, first seen in the "miniaturizer" room and later in scenes set outside the lung and inside the inner ear, when the cast was to be seen "swimming" (actually suspended by wires) outside the submarine. The full-size Proteus mockup contained all the interior sets that the actors are seen in to represent the interior of the submarine, with sections that could be pulled out to allow for cameras and crew to film the interior. The submarine was also constructed in miniature, including a large miniature around five feet in length that could be flown on wires in the abstract sets representing the inside of the human body. The heart and brain sets built to accommodate the 5-foot miniature filled a soundstage on the Fox lot—these were filmed "dry for wet", with floating, blob-shaped elements meant to be blood cells filmed separately and composited over the footage. A smaller, 18-inch miniature of the Proteus was constructed to operate in liquid for a shot of the submarine bursting through an arterial wall early in the film. A tiny Proteus miniature just a few inches in length was made for the miniaturization sequence to show the ship being picked up by a "precision handling device" and dropped into a large glass cylinder that was then miniaturized to become part of a syringe that would inject the Proteus into the brain-injured scientist. The film starred Stephen Boyd, making his first Hollywood film in five years. It was the first role at Fox for Raquel Welch, who was put under contract to the studio after being spotted in a beauty contest by Saul David's wife. For the technical and artistic elaboration of the subject, Fleischer asked for the collaboration of two people of the crew that he had worked with on the production of 20,000 Leagues Under the Sea, the film he directed for Walt Disney in 1954. The designer of the Nautilus from the Jules Verne adaptation, Harper Goff, also designed the Proteus; the same technical advisor, Fred Zendar, collaborated on both productions. At one point in the film's preproduction it was positioned as one of the Derek Flint spy spoof films starring James Coburn, which were produced by 20th Century Fox and Saul David. Several script pages sampled in the bonus features of the 2012 DVD release of Fantastic Voyage show Stephen Boyd's Charles Grant character (who, like Flint, is a secret agent) being identified as Flint, and some of Flint's wisecracks about not wanting to be miniaturized survive to be uttered by Boyd's Grant in Fantastic Voyage. Years later comic actor Mike Myers proposed making an installment of his own Austin Powers spy spoof films called Shagtastic Voyage, in which Austin Powers would be injected into the body of Dr. Evil. The military headquarters is 100 m × 30 m (328 ft × 98 ft), and the Proteus 14 m × 8 m (46 ft × 26 ft). The artery, in resin and fiberglass, is 33 m (108 ft) long and 7 m (23 ft) wide; the heart is 45 m × 10 m (148 ft × 33 ft), and the brain is 70 m × 33 m (230 ft × 108 ft). The plasma effect was produced by chief operator Ernest Laszlo via the use of multicolored turning lights, placed on the outside of translucent decors. "There are no precedents so we must proceed by trial and error", said David. Frederick Schodt's book The Astro Boy Essays: Osamu Tezuka, Mighty Atom, and the Manga/Anime Revolution claims that Fox had wanted to use ideas from an episode of Japanese animator Osamu Tezuka's Astro Boy in the film, but it never credited him. Isaac Asimov, asked to write the novelization from the script, declared that the script was full of plot holes, and received permission to write the book the way he wanted. The novel came out first because he wrote quickly and because of delays in filming.

The score was composed and conducted by Leonard Rosenman. The composer deliberately wrote no music for the first four reels of the film, before the protagonists enter the body of Dr. Jan Benes (Jean Del Val). Rosenman wrote that "the harmony for the entire score is almost completely atonal except for the very end when our heroes grow to normality".

The film received mostly positive reviews and a few criticisms. The weekly entertainment-trade magazine Variety gave the film a positive pre-release review, stating: "The lavish production, boasting some brilliant special effects and superior creative efforts, is an entertaining, enlightening excursion through inner space—the body of a man." Bosley Crowther of The New York Times wrote: "Yessir, for straight science-fiction, this is quite a film—the most colorful and imaginative since Destination Moon" (1950). Richard Schickel of Life magazine wrote that the rewards would be "plentiful" to audiences who get over the "real whopper" of suspended disbelief required. He found that though the excellent special effects and sets could distract from the scenery's scientific purpose in the story, the "old familiar music of science fiction" in lush new arrangements was a "true delight", and the seriousness with which screenwriter Kleiner and director Fleischer treated the story made it more believable and fun. Schickel made note of, but dismissed, other critics' allegations of "camp". As of 2025, the film holds a 91% approval rating at review aggregator Rotten Tomatoes from 35 reviews, with an average rating of 7/10. The website's critics consensus reads: "The special effects may be a bit dated today, but Fantastic Voyage still holds up well as an imaginative journey into the human body." Metacritic, which uses a weighted average, assigned the film a score of 72 out of 100, based on 9 critics, indicating "generally favorable" reviews.

According to Fox records, the film needed to earn $9,400,000 in rentals to break even and made $8,880,000, meaning it initially showed a slight loss, but television sales moved it into the black, and subsequent home video sales were almost entirely profit.

The film won two Academy Awards (1966) and was nominated for three more:

Won: Best Art Direction – Color (Jack Martin Smith, Dale Hennesy, Walter M. Scott, Stuart A. Reiss) Best Special Effects (Art Cruickshank) Nominated: Best Cinematography (Ernest Laszlo) Best Film Editing (William B. Murphy) Best Sound Editing (Walter Rossi)