Before any part of the episodes were written, the guests were interviewed by a crew member, sometimes wearing the Space Ghost costume made famous by Andy Merrill in some Cartoon Planet (1995) intros. The interviewer also instructed the guest to address him as "Space Ghost" to maintain continuity. After an interview was done, the writing crew went back over it, taking pieces out of context and out of order, assembling them into the responses to Space Ghost and the rest of the cast. Most of the show's earlier guests assumed they were participating in a relatively straightforward interview. As the series became more popular, however, more and more guests became at least peripherally familiar with what was going on.

Originally created as a Cartoon Network promo. The programmers had been using old cartoon shows and re-engineering them to act as hosts for a day. Each classic cartoon had its own gimmick; Space Ghost's segment was made a late night talk show and, for rhyme's sake, was called "Space Ghost Coast to Coast".

In the show's early stages of production, Hervé Villechaize was set to be Space Ghost's sidekick, but these plans were halted when the actor tragically committed suicide.

Space Ghost interviewed Tommy Wiseau in a series of bumpers for Adult Swim's April Fools' Day 2010 showing of The Room (2003).

The guests and the regulars are often asked whether they are getting enough oxygen.

The DVDs for the show have run into problems because some of the interviews weren't licensed for home video.

All episodes were made available for free for a limited time on Adult Swim's website following the 2016 death of C. Martin Croker, animation director and voice of Zorak/Moltar.

Space Ghost Coast to Coast was the only Cartoon Network original series that moved to Adult Swim, until 2017, when Samurai Jack premiered its fifth and final season.

The series featured 5 Academy Award winners: Charlton Heston, David Byrne, Michael Moore, Goldie Hawn and Steven Wright as well as 5 Academy Award nominees: Peter Fonda, Willie Nelson, Carol Channing, Michael McKean and Björk. Additionally, Academy Award Winners Denzel Washington and Emma Thompson were both interviewed for the two unaired pilots.

Space Ghost Coast to Coast ran for almost 10 years. It remained Cartoon Network's longest running original series, until Ed, Edd n Eddy surpassed it in 2009.

The first three volume DVDs were released in stores, Volume 1 has various episodes from the first two seasons of the show and included the first episode of season three as the last episode on the set, while volumes 2 and 3 had the entire third and fourth seasons, with some editing done so no copyrighted footage was included on some episodes. Volumes four and five, however, were released exclusively at the Adult Swim website, where Volume 4 had all of season five and Volume 5 had the complete sixth and seventh seasons. Volume 6, which would have contained all seven episodes of the eighth season, the final season, has not had a proper release on DVD. While there was an option to make your own DVD on Adult Swim's website back in 2011 and 2012, where the entire series's television run was available to put onto DVDs, and fans could then own all the episodes that were either not on DVD for copyright or other legal reasons, such as certain guests not giving permission to license their interview for the episode they were in to be released on DVD, or episodes that were edited and were now unedited and shown as they were on TV. However the shop section on Adult Swim closed in 2012 and as a result the DVD sets released online are now out of print. The series is available on iTunes, but some episodes like The Mask and A Space Ghost Christmas are omitted. As of now, there are no plans to release the final season or the complete series on DVD or Blu-Ray in a box set.

85 episodes available on HBO Max. Seasons 1-8, incorrectly stated as Seasons 1-9, due to Adult Swim's error in numbering the episodes as the fourth season finale is now put as the fifth season premiere as well as the last two episodes of season eight are now taken away and called the entire ninth season for no reason.

In 2006, Space Ghost Coast to Coast was revived as a web series on GameTap. The episodes were typically shorter than the televised episodes.

Space Ghost Coast to Coast had a total of three runs. The first of which debuted on Cartoon Network on April 15, 1994, and originally ended on December 17, 1999 but Cartoon Network revived the series May 7, 2001, and moving the show to Adult Swim September 2, 2001 during its launch; afterwards, the show ended its second run on April 12, 2004, days before its 10th anniversary. However, the series was revived the second and last time as a web series on GameTap from May 30, 2006 to May 31, 2008.

Space Ghost Coast to Coast was the only Cartoon Network original series to be created by one of their executives until 2004, when Sam Register created Hi Hi Puffy AmiYumi.

The only bonafide television talk show hosts who made guest appearances in this series were John Henson, Conan O'Brien and Jerry Springer.