The show began in 1983 as The Morning Show, a local New York program on WABC-TV with Philbin and Cyndy Garvey as co-hosts. They were previously co-hosts on A.M. Los Angeles, a similar program on KABC-TV in Los Angeles. Ann Abernathy took over Garvey's co-hosting position in 1984. Gifford, then known as Kathie Lee Johnson from her first marriage, replaced Abernathy on June 24, 1985, and the show—which had held its own against Phil Donahue's show in the local market—took off.
On September 5, 1988, Buena Vista Television began syndicating the show nationwide. (In 1996, BVTV's parent company Disney would acquire ABC, WABC's parent company.) The title was changed to Live with Regis and Kathie Lee. Viewers embraced the show, making it a popular staple of daytime TV. On February 29, 2000, Gifford decided to leave the show to pursue her singing career, and spend more time with her family. Her last show was on July 28, 2000.
After Gifford's departure, Philbin continued with the show and began a search for another co-host. The show was renamed Live with Regis, as Philbin hosted alone, with his wife Joy Philbin or with varying guest hosts including everybody from the cast of Survivor to The Daily Show's Jon Stewart. During this time, Philbin won the Daytime Emmy for Outstanding Talk Show Host, and was also hosting ABC's enormously popular Who Wants to Be a Millionaire. During "auditions" for co-hosts, Kelly Ripa became a favorite and front-runner, especially after a segment on the first episode on which she was a guest host on November 1, 2000. Psychic Char Margolis correctly predicted that Ripa was pregnant; Ripa had only told a small circle of friends about the pregnancy, and not ABC (as she was an actress on All My Children at the time) or the public.
Ripa was named the permanent co-host on February 5, 2001, and began her duties that day. Since Ripa took over, the show's ratings have increased to much higher levels, according to E!. Kathie Lee Gifford returned as a special co-host alongside Regis and Kelly on September 14, 2007, to celebrate Live’s 20 years in national syndication.
The show is still owned and produced by WABC-TV, and shares the same studio as WABC's venerable Eyewitness News broadcast. Not seen in the nationally syndicated show is a WABC Eyewitness News update, which is produced from its newsroom, as are all of its updates during Good Morning America due to the shared studio situation. In the beginning of the 2007-2008 television season WABC-TV has confirmed that Eyewitness News will once again acquire all of the current studio (TV13 and TV14), and Live with Regis and Kelly will move to the set used for the unsuccessful The Tony Danza Show located in the same building, or in the nearby vicinity. Construction on both sets began in the summer of 2007, and the new sets should have their debut in 2009.
Philbin announced on March 12, 2007, that he would undergo heart bypass surgery the following Wednesday after experiencing symptoms of heart disease. Guest co-host, Jimmy Kimmel, hosted alongside Ripa during Philbin's absence.  He returned to his hosting duties on April 26, 2007, 6 weeks and 1 day after his surgery.