In 1944, Messick joined the US Army, performing for troops as a part of the Special Services for 20 months. Messick’s first big break came when he was hired by the Mutual Broadcasting radio station in Los Angeles, where he played Raggedy Andy and Farmer Seedling on the radio series The Raggedy Ann Show.

Messick married Helen McHugh on October 10, 1949, and they remained married until Messick’s death on October 24, 1997. They have one son, Timothy.

When William Hanna and Joseph Barbera formed their own animation studio, Hanna-Barbera, in 1957, Messick and Butler became a voice-acting team for the company. Messick and Butler’s first collaboration was Ruff and Reddy. Messick was Ruff the cat and the Droopy-sounding Professor Gizmo, while Butler played the dog Reddy. Messick also narrated the show, which had a serialized storyline. From 1958 to 1959, Messick played Tadpole in the animated television series Spunky and Tadpole, produced by Beverly Hills Productions.

Messick was eventually featured as Ricochet Rabbit in Ricochet Rabbit (1964–65), while Deputy Droop-a-Long was voiced by Mel Blanc. He did the voices of the title character in Precious Pupp and Shag Rugg from Hillbilly Bears, and both segments from The Atom Ant/Secret Squirrel Show. In 1966, Messick took over the roles of Atom Ant and Mr. Peebles of The Magilla Gorilla Show from Howard Morris, who had left Hanna-Barbera.

In 1969, he was cast as the cowardly canine Scooby-Doo on Scooby-Doo, Where Are You!. He voiced him through all of the various versions of Scooby-Doo: on television in numerous formats from 1969 until his retirement, including television films, and a number of commercials, as well. In 1970, he voiced Sebastian on Josie and the Pussycats, and reprised the role in its spin-off Josie and the Pussycats in Outer Space two years later, as well as voicing the new alien character, Bleep. From 1980–1988, he voiced Scooby’s nephew, Scrappy-Doo, having taken over the role originated by Lennie Weinrib in 1979; he continued to voice Scooby-Doo when A Pup Named Scooby-Doo came along from 1988–1991.

In Hong Kong Phooey, he was the voice of Spot the Cat, a faithful sidekick that was the one who foiled the villain’s plans, though he let the clueless title character take the glory. In 1977, he voiced Balin and a few incidental characters in the first animated adaptation of The Hobbit by J. R. R. Tolkien.

He played Papa Smurf on The Smurfs from 1981–1989 and Ratchet (the Autobot doctor), Gears, and Constructicon Scavenger on The Transformers. In 1985, new episodes of The Jetsons were produced and Messick returned as Astro, RUDI, Mac, and Uniblab, a pesky robot that worked for Mr. Spacely.

He also starred in the Masters of the Universe Golden Book video as He-Man. In 1985, he voiced Louie and Snichey in The Pound Puppies TV special, in 1988, he had an uncredited role as the Pimp of the Year pageant announcer on I’m Gonna Git You Sucka, and he returned to his role of Benton Quest on The New Adventures of Jonny Quest (1986–1987).

From 1990–1995, he voiced Hamton J. Pig in Amblin’s Tiny Toon Adventures and its spin-offs. Around that time, he also returned as the voice of Droopy for Tom & Jerry Kids and Droopy, Master Detective. On the 1995 Freakazoid! episode “Toby Danger/Doomsday Bet”, a spoof of Jonny Quest, he played Dr. Vernon Danger, a parody of his own Dr. Benton Quest.

On October 12, 1996, he had a “retirement party” at his favorite Chinese restaurant (Joe Barbera personally sent a limo to Messick and his wife, and the two were chauffeured). Many of his companions and peers during his career who had come to pay tribute to him included Henry Corden, Casey Kasem, Lucille Bliss, Maurice LaMarche, Gregg Berger, Neil Ross, June Foray, Sharon Mack, Greg Burson, Walker Edmiston, Marvin Kaplan, Gary Owens, Howard Morris, Teresa Ganzel, Jean Vander Pyl, and Myrtis Martin Butler (Daws’ widow).

Messick suffered a second stroke and died on October 24, 1997, in Salinas, California. He was 71 years old. He was cremated, and his ashes were scattered into the Pacific Ocean at the Point Lobos State Reserve.

Since Messick’s death in 1997, Hadley Kay, Scott Innes, Neil Fanning, and Frank Welker have all voiced the role of Scooby-Doo. In 1998, Scooby-Doo on Zombie Island was dedicated to his memory. In 2011, Jonathan Winters (who voiced Grandpa Smurf in the television series) became Messick’s successor as the voice of Papa Smurf in The Smurfs and its 2013 sequel. Winters died after finishing his work on the latter film.