Gibbons has been married four times; she was married to John Hicks from 1980 to 1982. From 1989 to 1991, she was married to British actor Christopher Quinten, with whom she has a daughter, Jordan Alexandra (Lexi) Gibbons. She was married to actor Stephen Meadows from 1991 to 2005, and they had two sons, Troy and Nathan Daniel. In 2011, she married New York Times best selling author, Steven Fenton, in Beverly Hills. Fenton is the son of the former mayor of Beverly Hills, Frank M. Fenton.

In 1983 Gibbons joined WCBS-TV in New York City, where she became a host on Two on the Town, a program modeled after PM Magazine; her co-host was Robb Weller. The following year, they would both join Entertainment Tonight, with Gibbons as a reporter and co-anchor of the program's weekend edition. Concurrently hosted, Leeza was her own NBC/syndicated talk show, which ran from June 1993 to September 2000. The show originated as John & Leeza from Hollywood, a talk show with former Entertainment Tonight co-host John Tesh. Tesh was dropped from the show after seven months, and Gibbons hosted solo for the remainder of the series. From 2001–2003, Gibbons was the host and managing Editor of the television show 'Extra'. In 2011, she pulled down double duty (again) as the host of the PBS show My Generation (2011–2014) and as co-host and executive Producer of the syndicated newsmagazine show America Now (2011–2015).

In the early to mid-1990s, Gibbons partnered with Guthy Renker and became a trailblazer in the world of direct response. She was the first television star on a daily show to be featured in an infomercial as she starred in back-to-back blockbusters (Personal Power 2 and Get the Edge) with a young Tony Robbins.

In early 2000s, Gibbons launched her mineral makeup line, Sheer Cover Studio, with Guthy-Renker. Gibbons said, "Sheer Cover is not just a makeup product, it's a transformative experience for women who have serious skin issues like sun damage, birth marks, scars and acne or just for any woman who wants natural looking skin that glows with a healthy radiance." Presently, Sheer Cover continues to be sold around the world.

On November 14, 2007, California Governor Arnold Schwarzenegger announced the appointment of Gibbons to the board that oversees California's stem cell research agency. Gibbons fills a slot designated for a patient advocate for Alzheimer's as the result of her nonprofit group, Leeza's Place, which is aimed at caregivers for persons with memory disorders. Gibbons' efforts with memory disorders grew out of her own family's experience with her mother who was diagnosed with Alzheimer's disease and died in May 2008.

In May 2009 Gibbons' new book, Take Your Oxygen First: Protecting Your Health and Happiness While Caring for a Loved One with Memory Loss, tells the story of Leeza's family's personal struggle with Alzheimer's disease after her mother's diagnosis. She provides practical advice on how caregivers and their families can (and must) take care of their own physical, emotional and spiritual needs in order to give better care to their loved ones who may be suffering with a memory loss disorder.

In 2013, Gibbons won her first Daytime Emmy Award for Outstanding Lifestyle/Travel Host for the PBS series My Generation.

In 2015, she won the NBC reality game-show series Celebrity Apprentice, beating out TV news personality Geraldo Rivera. She became the second female winner of the show, after Joan Rivers.

In 2016, Gibbons and Guthy-Renker launched their latest infomercial together, Dr Denese Skinscience.

She began co-hosting the Rose Parade on January 2, 2017.