Intended as a nighttime companion to The Mike Douglas Show and succeeding Steve Allen and Regis Philbin in the time slot, this version of the Griffin program aired in multiple time slots throughout North America (many stations ran it in the daytime, and other non-NBC affiliates broadcast it opposite The Tonight Show Starring Johnny Carson).
That same year, Griffin relocated his show from New York's Cort Theatre to CBS Television City in Los Angeles, without sidekick Arthur Treacher, who told him "at my age, I don't want to move, especially to someplace that shakes!".
Griffin’s idea of the perfect show was to have as many diverse guests as possible, from entertainers to scientists, Hollywood glamour to Vegas variety, and from comedians to political leaders.
For over a quarter of a century, more than 25,000 guests appeared on The Merv Griffin Show including numerous significant cultural, political, social and musical icons of the 1960s, 1970s and 1980s.
Four American presidents–Richard Nixon, Gerald Ford, Jimmy Carter and Ronald Reagan appeared, as did Martin Luther King Jr., Rosa Parks, Jonas Salk and Robert F. Kennedy.
Legendary actors and directors who appeared on the program include Orson Welles, John Wayne, Judy Garland (who took over as guest hostess for Griffin on one program in January 1969, six months before her death), Doris Day (Griffin's longtime friend), Robert De Niro, Tom Cruise, Sophia Loren, George Clooney, Tom Hanks, Gene Wilder, Francis Ford Coppola, Dustin Hoffman, Clint Eastwood and Grace Kelly.
Musical performers and composers ranging from Devo to Aretha Franklin with Bobby Vinton, Andrew Lloyd Webber, Marvin Gaye, Merle Haggard, The Bee Gees and Johnny Cash, among others, all guesting.
Sports figures interviewed by Griffin on the show include Muhammad Ali, Joe Namath, Roger Maris, Willie Mays and Reggie Jackson.
Other notable guests that rarely made TV appearances showed up to talk to Griffin include Maharishi Mahesh Yogi, Andy Warhol, Norman Rockwell and Salvador Dalí.
Andy Kaufman's appearance on the show was a feature in the plot of the 1999 biopic Man on the Moon, with Griffin being played by character actor Mike Villani.