Muttley first appeared in Wacky Races in 1968, as the sidekick of the accident-prone villain Dick Dastardly. While Dick was created as the equivalent of Professor Fate from the 1960s movie The Great Race, Muttley mirrored the film's character of Max Meen. Dastardly and Muttley were paired together in various later Hanna-Barbera series as bumbling villains.

As his name implies, Muttley is a snickering, mixed breed dog, identified in the Wacky Races segment Dash to Delaware as a mix of bloodhound, pointer, Airedale, and hunting dog. During Dastardly and Muttley in Their Flying Machines, in the episode Sappy Birthday, Muttley shows a calendar where April 16 is marked; his birthday. In an audio commentary for Dastardly and Muttley, the designers comment that they conceived of Muttley's shape as what a dog would look like if he were a tank-styled vacuum cleaner.

Muttley does not really talk; his main examples of speech are his trademark wheezy snicker[14] (usually at Dick's expense, who sometimes retaliates by thumping him on the head) and a mushy, sotto voce grumble against an unsympathetic or harsh Dick (usually along the lines of Snazza frazza rashin' fashin' Rick Rastardly!). Don Messick had previously used Muttley's distinctive laugh for a recurring antagonist for Huckleberry Hound in the form of a black and white dog who enjoyed antagonising Huck the mailman, dogcatcher, barbecuer, etc. Messick also used the same laugh for the character of Griswold in an episode of Top Cat, then for an embryonic version of Muttley (called 'Mugger') appearing in the 1964 movie Hey There, It's Yogi Bear,as well as for another Hanna-Barbera canine, Precious Pupp, in 1966. He also repurposed it for Alexandra Cabot's cat Sebastian on Josie and the Pussycats in 1970.

Muttley (who turned from a bluish hue to a dusty brown wore only a collar in Wacky Races, but in Dastardly and Muttley in Their Flying Machines, he donned a World War I style aviator's cap and scarf, and served as a flying ace along with Dastardly and two other pilots as members of the Vulture Squadron. In this spinoff, he also sported many medals and constantly demanded new ones from Dastardly for following his commands. Similarly, Dastardly frequently ripped medals off Muttley's chest as punishment for his incompetence. And it was upon joining Dastardly and Muttley in Their Flying Machines that Muttley gained the ability to fly in brief spurts by spinning his tail like a propeller.

Muttley also enjoyed his own short segment in the series Magnificent Muttley, where he would engage in Walter Mitty-style fantasies. The designers speculated that Muttley was popular that the producers wanted to give Muttley some time as a solo character.