Frank Welker was born in Denver, Colorado. Before he began his career as a voice actor, Welker was a live-action character actor, and appeared in such films as Elvis' The Trouble with Girls. Welker's longest running role is also one of his earliest voice-over roles: as Fred Jones, the level-headed leader of the mystery-solving team from Hanna-Barbera's Scooby-Doo, Where are You!. He began the role in 1969, and Welker has continued to perform it through most of the show's various spinoffs and versions. This also includes many parodies and cameos of the character in other cartoons.

In the 1980s, Welker voiced Megatron, Soundwave and his cassettes, and Galvatron (Season 3) in the Transformers cartoon. In this he formed a team with Chris Latta, who voiced Starscream, Megatron's second-in-command. In 1988, Welker did the voice of Rulon leader Krulos in the TV-series Dino-riders. In this cartoon he again formed a team with Chris Latta, who (coincidentally?) voiced Rasp, Krulos' second-in-command. In G.I. Joe, Welker also teamed with Latta. (Other actors who featured in Transformers, Dino-riders and G.I. Joe are Jack Angel, Charlie Adler and Peter Cullen.) He also provided the voice of Dr. Ray Stantz and the garbled sounds of Slimer in The Real Ghostbusters and its several later versions.

Welker has been referred to as a "voice acting god" in Hollywood for the sheer number of voices he has done - over 1,200 - ranging from his work on Scooby-Doo to the present day with his many roles in cartoons (Lilo & Stitch: The Series), films (The Cat in the Hat), and computer games (the Baldur's Gate series). In The Transformers, he voiced nearly all of the original Decepticons. With the release of the film, he took on the role of the Autobot Wheelie, and afterwards, took over the role of Galvatron from Leonard Nimoy. Having already provided the screams for Nimoy's character Mr. Spock in Star Trek III: The Search for Spock, this marked the second time he had inherited a role from Nimoy. Welker did more live action movies during the 1990s. Among his work includes vocal effects for the character Goro in 1995's Mortal Kombat, the movie being based on Midway's popular fighting game, and Welker voiced the Devil Malebolgia in 1997's Spawn, the movie based on the very popular Todd McFarlane comic books. Welker also provided the voice (both speaking and non-speaking) of Nibbler in the cartoon TV series Futurama.

As of 2002, Welker is the voice of both Fred Jones and Scooby-Doo in What's New Scooby-Doo?, the latest series-based spinoff to Scooby-Doo, Where Are You!. Welker also voices King Bowser in 2003's Mario Party 5, and 2005's Super Mario 64 DS.