James Doohan was offered the part of Chief Sharkey, but turned it down, because that same week he was offered and accepted the role of Chief Engineer Montgomery Scott of the Starship Enterprise on Star Trek (1966), for which he became famous.

The props used in this show, (such as the computers and guns) also were used in Lost in Space (1965), The Time Tunnel (1966), Land of the Giants (1968), and Batman (1966).

The season two opener, "Jonah And The Whale", was the first episode to be broadcast in color. Seaview was redesigned with only one set of observation windows and a hatch for the flying sub, although stock footage was used throughout seasons two through four, showing the sub with three or six windows. New uniforms appeared also, as well as the flying sub. Over the course of seasons two through four, there were six different flying sub models used for filming.

At first, David Hedison turned down the role of Lee Crane, until he learned that Richard Basehart was signed to play Nelson.

This is the longest-running of all Irwin Allen-produced science fiction series. It ran for four seasons, from 1964 to 1968.

Late in the filming of the second season, Richard Basehart fell ill during the filming of the episode "The Monster's Web", and was unable to complete that episode, and work on the next two. "The Monster's Web" was re-written to minimize the part of his character, Admiral Nelson (knocked out of action in the first act), with a stand-in used for many shots with his face hidden and lines dubbed. The next episode, "The Menfish", had Nelson away, and his lines reassigned to guest character Admiral Park (Gary Merrill). The following episode, "The Mechanical Man", had Nelson still away, and reassigned his lines to Captain Crane (David Hedison) and Crane's lines to Commander Morton (Robert Dowdell). Basehart returned in time to appear in the season finale, "The Return of the Phantom".

The Seaview had a sister sub called the "Polydor" that was destroyed in the second episode.

During the 1965 season of the series, Susan Flannery was considered for a recurring role as Admiral Nelson's secretary, serving both as an on-shore ally to the adventures, and as occasional romantic interest for Captain Crane. The plans were dropped, after demographics showed the series was more popular with children than adults.

Henry Kulky was chosen as a series regular in the role of Chief Curley Jones. The role was cut short when Kulky was stricken by a fatal heart attack in February 1965 that ended his life and career, which included over one hundred features and television episodes.

Del Monroe was the only actor to appear in the movie and television versions, playing virtually the same character. He was Seaman Kowski in the movie, and Seaman Kowalski on the television show.

The series was satirized as "Voyage to See What's on the Bottom" by artist Mort Drucker and writer Dick De Bartolo in the March 1966 issue of MAD Magazine #101.

Every time the circuitry room is shown following an explosion, fire or combination of the two, the door is always unlocked.