The show was inspired by the 1812 novel The Swiss Family Robinson by Johann David Wyss, and its concept was rooted in a Gold Key comic book series called Space Family Robinson, whose rights were purchased by writer Hilda Bohem before Irwin Allen developed his own version.

CBS asked Irwin Allen to change the title to avoid confusion with the existing Gold Key comic book, and Bohem still filed a legal claim against Allen and CBS shortly before the series premiered in 1965; an agreement eventually let Gold Key add 'Lost in Space' as a subtitle to its comic.

An unaired pilot titled 'No Place to Hide' featured a ship called the Gemini 12 on a 98-year journey and depicted the Robinsons as a conflict-free happy crew with no Dr. Smith character; Smith and the Robot were added only after the series was commissioned, and the ship was renamed and redesigned as the Jupiter 2.

Jonathan Harris was credited only as a 'special guest star' in every episode despite Dr. Smith becoming a pivotal, central character.

The writers originally intended Dr. Smith to be a minor, temporary villain appearing only in early episodes, but Jonathan Harris, finding the role boring, began rewriting his lines and ad-libbing flamboyant dialogue, which transformed Smith into the show's defining comic character.

Jonathan Harris invented many of Smith's alliterative insults toward the Robot, such as 'You Bubble-headed Booby!' and 'Traitorous Transistorized Toad,' by lying awake at night dreaming them up; he later reused the line 'Oh, the pain... the pain!' while voicing the praying mantis Manny in Disney's A Bug's Life.

Props and monster costumes were frequently recycled between Irwin Allen's shows: a sea monster suit from Voyage to the Bottom of the Sea could be repainted for Lost in Space, and space monster costumes were reused as sea creatures on Voyage.

Filming took place at 20th Century Fox studios in Los Angeles; due to budget cuts in season 3, the Jupiter 2, campsite, and lower deck sets were moved from Stage 11 to the newly opened Stage 17.

The Chariot vehicle used in the series was an actual operational, cannibalized Thiokol Snowcat Spryte fitted with a Ford 170-cubic-inch inline-6 engine producing 101 horsepower.

The first season's personal laser gun prop was modified from a toy semi-automatic pistol made by Remco.

The season 3 theme music was newly composed by John Williams (credited as 'Johnny Williams') as part of the show's new direction, while the original pilot and much of season 1 reused Bernard Herrmann's score from The Day the Earth Stood Still (1951).

Lost in Space finished 35th in season one, 44th in season two, and 53rd in season three of the Nielsen ratings, and was reportedly the favorite childhood show of John F. Kennedy Jr.

The show was likely canceled due to rapidly rising costs—per-episode budgets grew from about $130,980 in season one to $164,788 in season three—and Irwin Allen became furious when CBS proposed a 15% budget cut for a potential fourth season.

Guy Williams grew embittered as the show became increasingly campy in seasons 2 and 3 while focusing on Dr. Smith, and he retired from acting and moved to Argentina after the series ended.

The catchphrase 'Danger, Will Robinson!' originated from the Robot's warnings in the series and was later used as the advertising slogan for the 1998 film, whose official website was 'www.dangerwillrobinson.com'.

For the 1998 film, Jonathan Harris was offered a cameo as the Global Sedition leader (eventually played by Edward Fox) rather than as Dr. Smith (played by Gary Oldman), but he turned it down, reportedly saying 'I play Smith or I don't play.'