In 1956 Byrnes got a non paying job in a summer stock theatre company in Connecticut, the Litchfield Community Playhouse. He began appearing in plays put on by the company as an actor. He tried Broadway without luck but managed to get some jobs in TV, starting with an episode of Crossroads in 1956. He could be seen in episodes of the shows Wire Service and Navy Log.

He tested for a role in Bernadine and Until They Sail but did not get it. A contemporary report described him as "a Tab Hunter type." However he did guest star on an episode of Cheyenne made by Warner Bros. They liked Byrnes' work and signed him to a long term contract in May 1957.

The show aired in October 1958 and was so popular Warners decided to turn it into a TV series 77 Sunset Strip. Byrnes' character became an immediate national teen sensation, prompting the producers to make Byrnes a regular cast member. They transformed Kookie from a hitman into a parking valet at a nearby restaurant who helped as a private investigator. Efrem Zimbalist, Jr., explained the situation to the audience:

Byrnes walked off the show in the second season, demanding a bigger part and higher pay. In November 1959 Warners put him on suspension. They eventually offered $750 a week but he refused. In April 1960 they came to terms and Byrne went back to work.

Owing to restrictions in his Warner Brothers television contract, Byrnes was forced to turn down film roles in Ocean's Eleven (1960), Rio Bravo (1959), North to Alaska (1960), and The Longest Day (1962). He tested for the role of John F. Kennedy in PT 109, but President Kennedy preferred Cliff Robertson.

Instead he guest starred on Lawman. Byrnes made a cameo as Kookie in Surfside Six and Hawaiian Eye, a 77 Sunset Strip spin off. He bought a story for Warners Make Mine Vanilla but it was not made. He threatened to punch a Photographer who was trying to take a photo of him getting a marriage licence. He did some summer stock in 1962 with his wife.

In August 1963 Byrnes bought up the remaining ten months of his contract with Warner Bros and left Sunset Strip. "No more hipster image for me," said Byrnes. "From now on I'd like to establish myself as a movie star."

Back in the US he made a pilot for a TV series, Kissin Cousins, based on the Elvis Presley film Kissin' Cousins (1964) with Byrnes to play the lieutenant played by Presley in the film. It did not go to series. Byrne starred in a beach party movie financed by Corman, Beach Ball (1965). He was in episodes of Mister Roberts, Honey West, and Theatre of Stars and did Picnic, Bus Stop, Sunday in New York, Sweet Bird of Youth and Cat on a Hot Tin Roof on stage in stock.

The Shadow of Kookie hung over him. "People think that's the only role you can play," he said in 1966. "Producers and Directors still think of me as the kid I played on the Strip. I've been offered other series but they've still wanted to cast me as the same kid."

Byrnes returned to Europe for several spaghetti westerns, including the 1967 films Renegade Riders, Any Gun Can Play and Red Blood, Yellow Gold. In 1969 he said he made more money in the preceding year than in his entire time on Warner Bros.

Back in the US he worked mostly in TV: episodes of Mannix, Love, American Style, The Virginian, Adam 12, and The Pathfinders. He was also in the TV movies The Silent Gun (1969) and The Gift of Terror.

Byrne was in the "Duo-Vision" horror film Wicked, Wicked in 1973, and as a TV interviewer in the David Essex film Stardust (1974).

In 1974, Byrnes hosted the pilots of Wheel of Fortune but he was replaced by Chuck Woolery.

Byrnes played the role of the Dick Clark-like dance-show host Vince Fontaine, host of National Bandstand, in the 1978 movie Grease.

The success of the film led to Byrne being cast in the lead of a TV series $weepstake$ but it only lasted nine episodes. He went back to guest starring in shows like CHiPs, B.J. and the Bear, House Calls, Charlie's Angels, Vega$, The Love Boat, Fantasy Island, Quincy M.E., The Master, Simon & Simon and Crazy Like a Fox. He had a small role in the Erin Moran film Twirl (1981) and the lead in Erotic Images (1983) with Britt Ekland.

Byrnes also appeared in Mankillers (1987), Back to the Beach (1987), Party Line (1988) and Troop Beverly Hills (1989).

One of his final roles was Shake, Rattle and Roll: An American Love Story (1998).

As a tribute to his enduring Celebrity and his iconic "Kookie" character, Byrnes has ranked #5 in TV Guide's list of "TV's 25 Greatest Teen Idols" (23 January 2005 issue). He wrote an autobiography in 1996 entitled Kookie No More.

Byrnes appeared during the Memphis Film Festival in June 2014, in which he was reunited with his former Yellowstone Kelly co-star Clint Walker.

Byrnes' son by Asa Maynor is Logan Byrnes, a television news anchor for Fox-11 News in Los Angeles, California. Previous to 2016, he was at Fox Connecticut since 2008.