Space Ghost Coast to Coast used the talk show format as its template, but subverted it regularly. Various celebrities appeared on the show as guests. They were shown on a TV screen next to Space Ghost's desk, and unlike the characters, they were not animated. In early episodes of the show, Space Ghost apparently believed his guests were other superheroes and usually opened the interview by asking them about their superpowers. His interactions with guests were almost always painfully awkward, and sometimes hostile. It was sometimes hard to tell if guests were aware of the nature of the program on which they were appearing. Their answers often did not match the questions coming from Space Ghost, because the questions were changed after the interview.

Space Ghost's relationship with his co-workers was even worse. His bandleader, an evil talking mantis named Zorak, and his director/producer, a red-helmeted lava man named Moltar, worked for Space Ghost as punishment for their crimes. They frequently disrupted the show and made no secret of the fact that they hated him.

Most episodes of Space Ghost Coast to Coast were about 15 minutes in length, although there were a few 30-minute episodes. Cartoon Network often aired two episodes back-to-back to make a 30-minute programming block. In the first few years of the show, Cartoon Network would show episodes of the original 1960s and 1980s Space Ghost cartoons (sometimes with an unusual added laugh track) after the 11-minute episode of Space Ghost Coast to Coast.

1080p Webrips