Kenny Powers, the series' protagonist, is the name of a real-life American stuntman who attempted to jump a portion of the St. Lawrence River in a rocket propelled Lincoln Continental. The stunt was conceived by a Canadian stuntman, Ken Carter. When it came time to jump, he backed out, and the crew contacted Kenny Powers, who then attended the jump, failing in a dramatic fashion.

The creators offered Walton Goggins a role on the third season of the show, but it wasn't possible, due to scheduling reasons.

When promoting the second season of this show on Jimmy Kimmel Live! (2003) season nine, episode thirty-two, Danny McBride revealed that season two was shot in a little over thirty days.

The show is named after the song "Eastbound and Down" by Jerry Reed. The show's creators initially weren't sure if they could keep this as the title without getting sued.

Don Johnson and John Hawkes, who play Kenny Powers' father and brother on this show, are only ten years apart in age in real-life.

The English teacher at the school which Powers substitute teaches, is named after one of Danny McBride's English teachers in high school.

In the season three finale, Kenny yells "I'm in a f***ing Cameron Crowe movie!" after abandoning his baseball career for April. Danny McBride appeared in the Cameron Crowe film, Aloha (2015).

In the Series finale, in the last few mins of the final episode. The scene in the alley is almost a direct copy of how Batman's parents died.....but with a Kenny Powers twist.