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The show premiered on NBC on March 30, 1964, hosted by Art Fleming, and lasted for 11 years. Merv wrote the 30-second piece of music heard during the show's Final Jeopardy! Round, and which later became the iconic melody of the theme for the show in the first part of Alex Trebek era.

In 1975, NBC canceled Jeopardy! after moving it twice on its daytime schedule, despite having an additional year on its network contract left to fulfill. Griffin produced the show's successor, Wheel of Fortune. Premiering on January 6, 1975, Wheel with Chuck Woolery and Susan Stafford as host and hostess, had mediocre ratings throughout its network run, yet was expanded to an hour, in response to the successful 60-minute version of The Price Is Right on CBS. It barely escaped cancellation in 1980, when NBC replaced all its other game shows with a daytime talk show starring David Letterman; NBC finally cancelled it in 1989, when CBS picked it up for a year, only to return to NBC, when the daytime version was finally cancelled for good in 1991. Wheel of Fortune became a phenomenon when on September 19, 1983, a nighttime version hit the syndication market with Pat Sajak and Vanna White as host and hostess, respectively. Two different revivals of Jeopardy! would be produced: one on NBC that ran for five months in late 1978/early 1979 with Art Fleming returning as host, and the other airing in first-run syndication beginning on September 10, 1984, starring Alex Trebek. Both the daytime syndicated version of Jeopardy! and the nighttime version of Wheel of Fortune remain on the air today in syndication.

In 1990, Griffin had an ambitious but unsuccessful attempt at adapting the venerable board game Monopoly into a game show of the same name. His biggest failure was a wild game show called Ruckus, which emanated from the Resorts International Hotel & Casino in Atlantic City, which he owned at the time. Involving slapstick stunts and a somewhat truncated version of his old Reach for the Stars, the show initially aired locally in New York, with the intent of national syndication early the following year. But the ratings were abysmal, and the plug was pulled on the show after several weeks. A national audience did get a look at it, via reruns that aired for a time on GSN.

Upon his retirement, Griffin sold his production company, Merv Griffin Enterprises, to Columbia Pictures Television unit for US$250 million on May 6, 1986, the largest acquisition of an entertainment company owned by a single individual at that time. Following the sale, Forbes named him the richest Hollywood performer in history. He retained the title of creator of both his game shows.

The two powerhouses spun off numerous programs, and Griffin often would sign on as a creative consultant. The spin-offs included Wheel 2000 on CBS in 1997 and the short lived Jep! on GSN in 1998, both for children; Rock & Roll Jeopardy! on VH1 in 1998 for purveyors of pop music trivia; a teen-oriented game called Click!, which introduced a youngster named Ryan Seacrest as its host, and in association with Wink Martindale, Headline Chasers in 1985.

On May 14, 2003, Griffin was honored with the Broadcast Music, Inc. (BMI) President's Award at its annual Film and Television Awards ceremony, for having created some of America's best-known game show melodies.

In 2007, Griffin's production company, Merv Griffin Entertainment, began pre-production on a new syndicated game show Merv Griffin's Crosswords (originally titled Let's Play Crosswords and Let's Do Crosswords). The show taped in Los Angeles after initial reports that it would be produced at WMAQ-TV in Chicago. The show was produced in association with Program Partners and the William Morris Agency and began airing September 10, 2007. NBC-owned-and-operated stations in New York, Los Angeles, Chicago, San Francisco and Dallas carried the show, with many stations airing two episodes per day.