The one-hour show was broadcast three times a day in some areas, and was seen all over the world on CNN International.
On June 29, 2010, King announced that the program would be coming to an end. The "final edition" of the program aired on December 16, but a new episode on the war against cancer aired two days later on December 18.
Larry King mainly conducted interviews from the studio, but he also interviewed people on-site in the White House, their prison cells, their homes, and other unique locations. Critics have claimed that Larry King asks "soft" questions in comparison to other interviewers, which allows him to reach guests who would be averse to interviewing on "tough" talk shows. His reputation for asking easy, open-ended questions has made him attractive to important figures who want to state their position while avoiding being challenged on contentious topics. When interviewed on Late Night with Conan O'Brien, King said that the secret to a good interview is to get the guest to talk about him- or herself, and to put oneself in the background pool.
A 1996 interview in the Washington Post had King note that he sometimes slips hard questions in between softballs. King prefers one-sentence questions. In the Post interview, King also proclaimed that he prepares as little as possible for each program, does not read the books of the authors he interviews, and admitted that the show was not journalism but "infotainment". He said that he tries to project an image of earnestness and sincerity in each interview, and the format of the show (King in suspenders instead of suit and tie, sitting directly next to the guest) reinforces that.
In response to "'softball' questions" accusations, King says, "I've never understood that. All I've tried to do is ask the best questions I could think of, listen to the answers, and then follow up. I've never not followed up. I don't attack anybody – that's not my style – but I follow up. I've asked people who say this, 'What's a softball question?' They'll say, 'You say to some movie star, what's your next project?' To me, that's not a softball. To me, that's interesting – what are you doing next?"
During major election coverage, the program may center on political analysis and commentary, as the show's airing generally coincides with the closing of polls in many states.
One of King's recurring topics is the paranormal. A frequent guest is John Edward of the popular television show Crossing Over with John Edward. Edward comes on the show and gives callers a free chance to supposedly communicate, via him, with their dead loved ones. King also had alleged psychics such as Sylvia Browne and James Van Praagh on from time to time to do readings and discuss the future. King sometimes allows skeptics such as James Randi to debate the psychics. In an April 2005 episode, King hosted a panel discussion regarding Evangelical, Catholic, Jewish, Muslim, and atheist views on the afterlife. King has also had topics about UFO's and Extraterrestrials where he pits experts against skeptics.
King is also frequently accused of pandering to sensationalist news stories; for instance, the death of Anna Nicole Smith took up much of King's shows after the event, causing the cancellation of numerous guests and interviews that were already scheduled, most notably Christopher Hitchens, who had intended to discuss the Iraq situation.
After the death of a prominent celebrity, King would either replay a recent program featuring said celebrity (for instance, after actor Don Knotts' death in 2006 King replayed the interview with Knotts and Andy Griffith taken several months before) or will bring on family members and close confidantes to the deceased to reminisce on the departed's life.
Each studio set features an identical colored-dot map of the world in the background and one of King's trademarks, a vintage RCA microphone (as seen in the title card), on the desk. The microphone is a prop, as King and his guests use lapel microphones.
On June 3, 1985, Larry King Live debuted on CNN, with then-Governor of New York Mario Cuomo as King's first guest.
To mark the 20th anniversary of the show, ABC's Barbara Walters was a guest host and interviewed King on his reflections of his career.
To mark 50 years in broadcasting, Larry King Live had a week long celebration that included a two hour CNN presents special and an hour of celebrity toast. The broadcast of this special week-long event was postponed due to the tragedy at Virginia Tech. XM Satellite Radio also featured a micro channel called "Larry!" that featured replays of the show along with interviews and the new material from the CNN anniversary shows.
On July 19, 2007, a frail Tammy Faye Messner made her final appearance on Larry King Live to talk about her battle with lung and colon cancer. She died the following day.
On February 12, 2010, during a discussion on Bill Clinton's latest heart procedure, Larry King revealed he had undergone a similar operation 5 weeks earlier. King had a heart attack in 1987 and said he had surgery to place stents in his coronary artery.
On December 16, 2010, the final episode of Larry King Live aired on CNN, with Ryan Seacrest and Bill Maher acting as co-masters of ceremonies, and surprise appearances by President Barack Obama, former President Bill Clinton, and network news anchors Barbara Walters, Diane Sawyer, Katie Couric and Brian Williams, among others. King says his final show was not a "good-bye" but rather a "so long", as he plans to move on and pursue other things. The final show attracted an audience of 2.24 million people, more than triple the program's usual audience of 672,000.
When King has been absent from the show, other interviewers have substituted for him.
On October 16, 1998, Wolf Blitzer hosted the show with the subject matter being the Matthew Shepard case. He also hosted the March 1 and March 19, 2008 episodes. In addition, he hosted again on March 22, 2010 and in August 2010.
Al Gore was supposed to host on May 6, 1999, with Oprah Winfrey as a guest and the topic was supposed to be the aftermath of the Columbine High School massacre. However, with Gore's candidacy for Presidency pending, CNN decided not to let him host as a result of the controversy.