By Agence France-Presse
Moore's eponymous sitcom -- set in Minneapolis -- ran for seven seasons in the 1970s and was named by Time Magazine as one of 17 shows that "changed television."
She died in hospital in Connecticut, according to media reports, after battling diabetes for years and undergoing brain surgery in 2011.
"Today, beloved icon Mary Tyler Moore passed away at the age of 80 in the company of friends and her loving husband of over 33 years, Dr. S. Robert Levine," her longtime representative Mara Buxbaum told AFP in a statement.
"A groundbreaking actress, producer, and passionate advocate for the Juvenile Diabetes Research Foundation, Mary will be remembered as a fearless visionary who turned the world on with her smile."
"The Mary Tyler Moore Show" was radical in its time -- featuring a single woman, living on her own, and chasing her dream as a television reporter.
It also spawned numerous spin-offs for its popular supporting cast of quirky, slightly neurotic characters, launching Moore's behind-the-scenes career.
As top executives of MTM Enterprises, Moore and then-husband Grant Tinker created and produced "The Mary Tyler Moore Show" and its spinoffs, and were also responsible for hit shows including "Hill Street Blues," "St. Elsewhere" and "Remington Steele."
'Effortless piece of cake'
"A minute's silence as we remembered one of the true greats of TV comedy," tweeted actor Stephen Fry, who was rehearsing on the Hollywood stage made famous by Moore's show.
Michael Keaton described her as "iconic, my boss, castmate and a friend" while filmmaker Kevin Smith said she was a "tireless defender of animals, and scourge of diabetes."
"Truly she turned the world on with her smile," he added, referring to the lyrics of her show's theme song.
Talk show host and actress Ellen DeGeneres said Moore "changed the world for all women" while Congresswoman Betty McCollum of Minnesota described the actress as one of the state's "favorite honorary daughters."
Moore's first big break came in 1961, when she played spunky stay-at-home wife Laura Petrie on "The Dick Van Dyke Show."
In the popular sitcom, the TV couple famously slept in separate twin-size beds, and Moore was limited to wearing capri pants in just one scene per episode.
Van Dyke said working with the "beautiful, bright and talented," Moore was "an effortless piece of cake."
Speaking at the 2012 Screen Actors Guild awards, where he presented Moore with a lifetime achievement award, Van Dyke said he initially had his doubts about the unknown 20-something, wondering, "Can she do comedy?"
- Emmy winner, Oscar nominee -
It turns out, he said, she could do "everything." She danced, sang, did slapstick, and was such a perfect onscreen match for him, Van Dyke said, that many viewers wondered whether the couple were also married in real life.
On the big screen, Moore starred opposite Elvis Presley in "Change of Habit," and with Julie Andrews in "Thoroughly Modern Millie."
She earned an Oscar nomination for her role in Robert Redford's searing family drama "Ordinary People."
She also took home numerous Emmy awards for her television work and a Tony Award for a Broadway performance in "Whose Life Is It Anyway."
Behind the scenes, Moore faced a number of personal difficulties, including an addiction to alcohol. Her only child, Richie, born during her first marriage to Richard Meeker, struggled with emotional issues and drug abuse.
He shot and killed himself in 1980, at age 24, in an incident that was officially deemed an accident.
Moore, who was born in New York and moved to California as a child, married her third husband, Robert Levine, in 1983. She was an active spokeswoman for animal rights and for diabetes, which she was diagnosed with in her 30s.
"(Diabetes) has taken a toll on her. She's not well at all," Van Dyke told the "Larry King Now" show in October 2015.
Gabrielle Carteris, president of the SAG-AFTRA actors' union, described Moore as a "television legend" who was an agent of change at a time when independence for women was not the societal norm.