He started as a member of Freddy Martin's orchestra, but became popular with nightclub audiences as a solo act. He scored a number one hit with I've Got a Lovely Bunch of Coconuts, which sold over three million copies. During one of his nightclub performances, he was discovered by Doris Day, who arranged for a screen test at Warner Bros. Studios, and he appeared in such films as So This Is Love (1953) and The Boy From Oklahoma (1954).

Meanwhile, he was also appearing regularly in such TV shows as The Arthur Murray Show and The Jack Paar Show. He eventually hosted a game show produced by Mark Goodson and Bill Todman, Play Your Hunch, from 1958 to 1962. The show appeared on all three networks, but primarily on NBC.

Griffin scored a coup when Jack Paar accidentally emerged onto the set of Play Your Hunch during a live broadcast (Paar was superstitiously trying to avoid the elevators at Rockefeller Center), and got him to stay for a spontaneous interview. He later substituted for Paar on The Tonight Show, leading NBC to offer him his own daytime talk show in 1962. That program failed, but NBC offered him the opportunity to host a new game show, Word for Word, in 1963, which Griffin produced as well. This led to his producing the far more successful Jeopardy! the following year.

Griffin would launch a syndicated 90-minute talk show in 1965, which aired in a variety of time slots throughout the country (many stations would run it in the daytime, some would air it opposite Johnny Carson's The Tonight Show, and it would air for many years on WNEW in New York in prime time). He was not shy on tackling controversial subjects, especially the Vietnam War, on all of his talk shows.

Griffin moved to CBS starting August 18, 1969, airing directly opposite Carson at 11:30 PM for three years. His role on the syndicated show was filled by David Frost. His show was produced in New York for the first year and from Los Angeles thereafter. In 1970, producers at NBC's "Today" show approached Griffin to co-host the show, but he never did. Griffin's show consistently finished behind Carson's in the ratings, and occasionally struggled to compete with Dick Cavett on ABC. At one point, CBS pressured Griffin to fire his long-term sidekick Arthur Treacher, who had been his television mentor, but that did not help. In 1972, the show was cancelled and he returned to syndication, displacing Frost. He eventually retired from the show in 1986.

In 1975, NBC cancelled Jeopardy! after moving it twice on their daytime schedule, despite having an additional year on its network contract. Griffin was allowed to produce the show's successor, which became Wheel of Fortune. A modest hit on daytime with Chuck Woolery and Susan Stafford as host and hostess, it became a phenomenon in 1983 in the syndication market, with Pat Sajak and Vanna White in the same respective roles. (Jeopardy would also start airing in first-run syndication in 1984.) Although Griffin had produced other game shows as well, these two would make him an extremely wealthy man.

Upon his retirement, he sold his production company, Merv Griffin Enterprises, to Coca-Cola's Columbia Pictures Television unit for $250 million, which was the largest acquisition of an entertainment company owned by a single individual at that time. He retained the title of executive producer of both shows.

Griffin also forayed into real estate, purchasing the Beverly Hilton Hotel in Beverly Hills. He also purchased Resorts Hotel and Casino in Atlantic City from Donald Trump in 1988. Unfortunately, this was not a successful purchase and the hotel was forced to file for Chapter 11 shortly thereafter. He also owns a ranch near Carmel, California where he raises thoroughbred racehorses, as well as St. Clerans Manor, an 18th century estate once owned by director John Huston which is located near Galway, Ireland. In the 1980s, Griffin purchased Paradise Island in the Bahamas for $400 million from Donald Trump, but later sold it for only $125 million.

In March 2001, Merv returned to singing with the release of his album It's Like a Dream.

Griffin has a son, Tony (by ex-wife Julann Griffin), and two grandchildren.