Born Beverly Louise Neill in Buffalo, New York, she was a telephone operator before taking up acting. Nicknamed "The Young Greer Garson," she became best known for her 19-year stint as Kitty Russell on the longest-running television drama, Gunsmoke. Miss Kitty was owner-operator of the Long Branch Saloon, from which she dispensed wisdom and whiskey while she carried on a mystery relationship with Dodge City's U.S. Marshal, Matt Dillon (played by James Arness). Blake's saloon-keeper character departed Dodge City in the series' 19th season after Matt experienced a final-straw brush with death that led Miss Kitty to leave a life of worrying about her lawman for unknown adventures outside of Kansas. Gunsmoke continued for one more year before CBS cancelled it after its 20th season, much to the surprise of the entire cast, including Arness.

Blake was inducted into the Western Performers Hall of Fame at the National Cowboy & Western Heritage Museum in Oklahoma City, Oklahoma in 1968, six years before the legendary John Wayne was inducted in 1974 and more than a decade before co-stars Arness, Ken Curtis, Dennis Weaver and Milburn Stone were inducted in 1981. In fact, with Tom Mix and Gary Cooper being inducted in 1958 and 1966 respectively, Blake was only the third Western performer to be inducted into the Western Performers Hall of Fame. Clint Eastwood was not inducted until 2000. Henry Fonda did not receive the honor until 2005.

After Gunsmoke, Blake went into semi-retirement at her home in Phoenix, Arizona, taking on only a few film or TV projects. A lover of animals, she joined with others to form the Arizona Animal Welfare League in 1971, today the oldest and largest "no-kill" animal shelter in the state. In 1985, she helped finance the start-up of the Performing Animal Welfare Society (PAWS) and devoted a great deal of time and money in support of its efforts, including traveling to Africa. In the early 1980s, Amanda was diagnosed with AIDS. It is unclear how she contracted it, but reportedly she believed she was infected by her fifth husband, who was reportedly bisexual. He died of the disease shortly after their marriage.

Blake died in Sacramento, California at the age of 60 from a type of viral hepatitis brought on by AIDS. She had previously battled cancer and was in remission. The media was originally told her cause of death was cancer, but in 1991, it was revealed that she died of AIDS.

In 1997, the "Amanda Blake Memorial Wildlife Refuge" opened at Rancho Seco Park in Herald, California. The refuge is a PAWS sanctuary for free-ranging, African, hoofed wildlife, most of whom were originally destined for exotic animal auctions or hunting ranches.

Due to her continuing role on Gunsmoke, Blake did not appear in many films. Among her credits are:

Lili (1953) Sabre Jet (1953) A Star Is Born (1954) High Society (1955) The Glass Slipper (1955) Betrayal (1974) B.O.R.N. (1988) The Boost (1988) Television Appearances: