Gifford was born Kathryn Lee Epstein in Paris, France, to American parents, Joan (born Cuttell; January 20, 1930 – September 12, 2017), a singer, and Aaron Epstein (March 19, 1924 – November 19, 2002), a musician and former US Navy Chief Petty Officer. Aaron Epstein was stationed with his family in France at the time of Gifford's birth. Gifford grew up in Bowie, Maryland, and attended Bowie High School.

Gifford's career took off in the 1970s as a vocalist on the game show Name That Tune with Tom Kennedy. In 1978, she joined the cast of the short-lived Hee Haw spinoff, Hee Haw Honeys.

During high school, Gifford was a singer in a folk group, "Pennsylvania Next Right", which performed frequently at school assemblies. After high school graduation in 1971, Gifford attended Oral Roberts University in Tulsa, Oklahoma, studying drama and music. During a summer in the early 1970s, she was a live-in secretary/babysitter for Anita Bryant at her home in Miami.

Kathie Lee married Paul Johnson, a Christian composer/arranger/producer/publisher in 1976. They gained fame in Christian music and appearing on covers of Christian magazines. But the marriage was strenuous from the start and in 1981, Paul decided to move out. The couple divorced in 1982.

She appeared as a spokesperson for Slim Fast diet shakes after her son Cody was born. She also was the face of Carnival Cruise Lines in the late 1980s and early 1990s, singing "If my friends could see me now!" In 1994, she appeared as herself in an episode of the NBC sitcom Seinfeld.

Following her divorce from her first husband Paul Johnson in 1983, Gifford met Sports commentator Frank Gifford during an episode of ABC's Good Morning America; they were married from 1986 until his death in 2015. At the time she was several months into her role as a full-time morning talk show personality.

On June 24, 1985, she replaced Ann Abernathy as co-host of The Morning Show on WABC-TV with Regis Philbin. The program went into national broadcast in 1988 as Live! with Regis and Kathie Lee, and Gifford became well-known across the country. Throughout the 1990s, morning-TV viewers watched her descriptions of life at home with Frank, her Sportscaster husband and son Cody and daughter Cassidy. Gifford left the show on July 28, 2000.

On October 18, 1986, Kathie Lee married a second time, this time to Frank Gifford, an American football player and television Sports commentator. It was his third marriage after marriages with Maxine Avis Ewart and Astrid Lindley. With Ewart he had three children.

Kathie Lee was 23 years Frank's junior when they got married. They had two children together, Cody Newton Gifford (born March 22, 1990) and Cassidy Erin Gifford (born August 2, 1993). Frank died on August 9, 2015 from natural causes at their Greenwich, Connecticut home, a week shy of his 85th birthday. In 2017, she released "He Saw Jesus", a very personal song Kathie Lee co-wrote (with Songwriter Brett James) and dedicated to her husband. All proceeds from the song went to the international evangelical Christian humanitarian aid charity Samaritan's Purse.

Regis Philbin and Kathie Lee were jointly nominated eight consecutive years in a row (1993 to 2000) for Outstanding Talk Show Host during the Daytime Emmy Awards.

In 1996 the National Labor Committee, a human rights group, reported that sweatshop labor was being used to make clothes for the Kathie Lee line, sold at Wal-Mart. The group reported that a worker in Honduras smuggled a piece of clothing out of the factory, which had a Kathie Lee label on it. One of the workers, Wendy Diaz, came to the United States to testify about the conditions under which she worked. She commented, "I wish I could talk to [Kathie Lee]. If she's good, she will help us."

She did a number of voice overs most notably as Echidna in the 1998 TV series Hercules and the follow up 1999 comedy-drama and animated television film Hercules: Zero to Hero.

Gifford has made guest appearances in films and television series, and has several independently released albums on CD, including 2000's The Heart of a Woman, featuring the single "Love Never Fails".

In September 2005 she became a special correspondent on The Insider, a syndicated entertainment magazine television show, ending her relationship with that program upon her co-hosting role with Today.

She played the role of Miss Hannigan in a concert performance of Annie at Madison Square Garden in December 2006.

On April 16, 2007, Gifford was a guest presenter at the Washington, D.C. Helen Hayes Award Ceremony, honoring contributions and professional accomplishments in theatre.

In 2008, Gifford and David Friedman wrote a junior high school musical entitled Key Pin It Real. The play depicts a coming-of-age story about a young girl named Key Pin. The first production took place in December 2008 in Kendallville, Indiana, at East Noble High School.

She has written two autobiographical books, Just When I Thought I'd Dropped my Last Egg: Life and Other Calamities in 2010 and The Rock, the Road and the Rabbi to be released in early 2018. She has also written a number of children's books.

In 2007, she premiered Saving Aimee, a stage musical about evangelist Aimee McPherson, at the Signature Theatre in Arlington, Virginia. The premiere starred Actress Carolee Carmello in the lead role. The show, now titled Scandalous: The Life and Trials of Aimee Semple McPherson, ran on Broadway from November 15, 2012, through December 9, 2012, with Carmello reprising her role as McPherson. On April 30, 2013, Carmello received her third Tony Award nomination for the performance.

She appeared as herself in the 2015 television film Sharknado 3: Oh Hell No!