The show stars the titular Ed (Sean Cullen), a cheerful but none-too-bright dog loved by everyone. Ed's best friend is his polar opposite Doug (Patrick McKenna) an intelligent but unlucky squirrel whom everyone calls "Buddy" but nobody likes. Despite their differences, Ed and Doug consider themselves best of friends and have many adventures - and misadventures - in their town of Swellville
Best Ed contains examples of:
- Butt-Monkey: Doug is vehemently despised by everyone in Swellville and extremely unlucky.
- Dogs Are Dumb: Ed isn't very smart in contrast to his best friend.
- Kindhearted Simpleton: Ed, which is part of the reason the people of Swellville all love him.
- Odd Friendship: Ed and Doug are polar opposites in both personality and lot in life, but consider each other best friends.
- World of Funny Animals: The inhabitants of Swellville are anthropomorphic animals.