The TV series was based on Irwin Allen's 1961 film of the same name, and since Allen created both, the show reused the film's sets, costumes, props, special effects models, and sometimes footage.

Voyage to the Bottom of the Sea was the first of Irwin Allen's four science fiction television series, alongside Lost in Space, The Time Tunnel, and Land of the Giants, and it became the longest-running of the four.

The pilot episode 'Eleven Days to Zero' was actually filmed in color but was broadcast in black-and-white to match the rest of the first season.

Chief 'Curly' Jones was permanently replaced by Chief Sharkey at the start of season two following the real-life death of actor Henry Kulky, who had portrayed Jones.

Richard Basehart was hospitalized for a bleeding ulcer during season two, forcing the production to use a stand-in for his previously filmed Flying Sub scenes and to write him out entirely for two episodes, with Gary Merrill guest-starring as a substitute admiral in one of them.

Season two's episode 'The Sky's on Fire' remade the storyline of Irwin Allen's original 1961 film, reusing considerable color footage from it, some of which had already appeared in earlier first-season episodes.

A new, darker theme composed by Jerry Goldsmith was introduced in the season two episode 'Jonah and the Whale' but was quickly dropped in favor of the original Paul Sawtell theme, though Goldsmith's suite continued to be used as incidental music, including a version re-orchestrated by Nelson Riddle for 'Escape From Venice'.

A recurring visual gag, nicknamed 'Seaview Rock and Roll,' had actors lurching in response to supposed impacts on the visibly static submarine set, a trick also used on Irwin Allen's Lost in Space according to co-star June Lockhart.