Leachman, the eldest of three sisters, was born in Des Moines, Iowa, the daughter of Cloris (née Wallace) and Berkeley "Buck" Leachman, who worked at the family-owned Leachman Lumber Company. She graduated from Roosevelt High School in Des Moines in 1944. She later majored in drama at Northwestern University and Illinois State University, where she was a member of Gamma Phi Beta and a classmate of future comic actor Paul Lynde. Leachman began appearing on television and in films shortly after competing in Miss America as Miss Chicago 1946. Before that she was very active at the Des Moines Playhouse starring in many productions.

After winning a scholarship in the beauty pageant, Leachman studied acting in New York City at the Actors Studio with Elia Kazan. Leachman was a replacement for Nellie Forbush during the original run of Rodgers & Hammerstein's South Pacific. A few years later, she appeared in the pre-Broadway production of William Inge's Come Back, Little Sheba, but left the show before it reached the Great White Way when Katharine Hepburn asked her to co-star in a production of William Shakespeare's As You Like It.

She appeared in many live television broadcasts in the 1950s, including such programs as Suspense and Studio One. She was also one of the Raisonette Girls in the 1960s. She made her feature film debut as an extra in the 1947 film Carnegie Hall, but had her first real role in Robert Aldrich's film noir classic Kiss Me Deadly, released in 1955. Leachman was several months pregnant during the filming, and appears in one scene running down a darkened highway wearing only a trenchcoat. A year later she appeared opposite Paul Newmanand Lee Marvin in The Rack (1956). She appeared with Newman again, in a brief role as a prostitute in Butch Cassidyand the Sundance Kid (1969).

She continued to work mainly in television, with appearances including the classic It's a Good Life episode of The Twilight Zone, in which she played Bill Mumy's mother; Rawhide; and Alfred Hitchcock Presents. Leachman appeared as Ruth Martin, Timmy's adoptive mom, in the last half of season four (1957) of Lassie. She was replaced by June Lockhart in 1958. In 1959, she appeared in an episode of One Step Beyond entitled The Dark Room, where she portrayed an American photographer living in Paris.

Leachman has won numerous awards during her lengthy career. She won an Oscar for Best Supporting Actress in The Last Picture Show (1971), based on the bestselling book by Larry McMurtry. She played the high school gym teacher's wife, with whom Timothy Bottoms' character has an affair. Director Peter Bogdanovich had predicted to Leachman during production that she would win an Academy Award for her performance. The part was originally offered to Ellen Burstyn who wanted another role in the film.

Leachman has also won a record-setting eight primetime and one daytime Emmy Awards and been nominated more than 20 times for her work in television over the years, most notably as the character of neighbor/landlady/nosy friend Phyllis Lindstrom on The Mary Tyler MooreShow. The character was a fixture on the program for five years and was subsequently featured in a spinoff series, Phyllis (1975–1977), for which Leachman garnered a Golden Globe award. The series survived just two seasons, partly due to the deaths of three cast members during its brief run: Barbara Colby, Judith Lowry and Jane Rose. Leachman would later play a hot cougar in the North Avenue Irregulars in 1979.

In 1977, she guest starred on The Muppet Show, episode 224. In 1978, she won the Sarah Siddons Award for her work in Chicago theatre. During the mid and late 1970s, she was featured in several Schoolhouse Rock episodes.

In 1986, Leachman returned to television, replacing Charlotte Rae's character Edna Garrett as the den mother on The Facts of Life. Leachman's role, as Edna's sister, Beverly Ann Stickle, could not save the long-running series, and it was canceled two years later.

She has voice-acted in numerous animated films, including My Little Pony: The Movie as the evil witch mother from the Volcano of Gloom, The Iron Giant, and most notably as the voice of the cantankerous sky pirate Dola in Hayao Miyazaki's 1986 feature Castle in the Sky. Dubbed by Disney in 1998, Leachman's performance in this film received nearly unanimous praise.

Leachman played embittered, greedy, Slavic “Grandma Ida” on the Fox sitcom Malcolm in the Middle, for which she won two Emmy Awards, both for Outstanding Guest Actress in a Comedy Series (once in 2002, then again in 2006). She was nominated for playing that same character for six consecutive years.

Later television credits include the successful Lifetime Television miniseries Beach Girls with Rob Loweand Julia Ormond Leachman was nominated for a SAG Award for her role as the wine-soaked, former jazz singer and grandmother Evelyn in the Sony feature Spanglish opposite Adam Sandler and Tea Leoni. She had replaced an ailing Anne Bancroft in the role. The film reunited her with her The Mary Tyler MooreShow writer-producer-director James L. Brooks. That same year she appeared with Sandler again, in the remake of The Longest Yard. She also appeared in Kurt Russell comedy Sky High as the school nurse with X-ray vision.

In 2005, she guest starred as Charlie Harper's neighbor Norma on Two and a Half Men.

In 2006, Leachman's performance alongside Sir Ben Kingsleyand Annette Bening in the HBO special Mrs. Harris earned her an Emmy nomination for outstanding supporting actress in a miniseries or TV movie as well as an SAG Award nomination for Outstanding Performance by a Female Actor in a Television Movie or Miniseries.

On May 14, 2006, she was awarded an honorary Doctorate in Fine Arts from Drake University.

Leachman has appeared in three Mel Brooks films. She played Frau Blücher in Young Frankenstein (1974), in which the mere mention of her character's name frightens all horses within earshot (an homage to a cinematic villain stereotype). She also appeared in High Anxiety (1977), as demented psychiatric nurse Charlotte Diesel, and as Madame Defarge in the segment of History of the World: Part I (1981) which parodied Dickens' A Tale of Two Cities.

She auditioned for a chance to revive her role from Young Frankenstein in the 2007 Broadway production opposite Megan Mullally(replacing formerly cast Kristin Chenoweth) and Roger Bart However, Andrea Martin was cast in the role. Mel Brooks was quoted as saying that Leachman, at 81, was too old for the role. "We don't want her to die on stage," he told columnist Army Archerd. However, due to Leachman's success on Dancing with the Stars, Brooks had reportedly asked her to reprise her role as Frau Blücher in the Broadway production of Young Frankenstein after Beth Leavel, who replaced Martin. The Broadway production closed before this could be realized.

She was a contestant on Season 7 of Dancing With The Stars, and was paired with Corky Ballas, the oldest of the professionals. She is the oldest person to ever compete on the show. Despite coming in last place for five weeks, she won the hearts of millions (including the judges who praised her entertainment skills) and was kept out of the bottom two due to the viewers' votes. Cloris soon became known for her wild antics such as grabbing her partner's crotch during the mambo and ripping off her wig during her jive. A breakthrough came in week 4 when Cloris received her highest score of the competition (22/30).

From 1953 to 1979, Leachman was married to Hollywood impresario George Englund. Leachman's former mother-in-law was character actress Mabel Albertson, best known for playing Samantha's mother-in-law on the Abcsitcom Bewitched. The marriage produced five children: Bryan, Morgan, Adam, Dinah and George Englund, Jr. Some of them are in show business. Her son Morgan played Dylan on Guiding Light throughout the 1980s and early 1990s.

Leachman's son Bryan died from a drug overdose on February 25, 1986. Some reports state that it was an overdose of ulcer medication, while others, such as in the Lifetime Television program Intimate Portrait: Cloris Leachman (in which Leachman participated), state that it was from cocaine.

The Englunds were Bel Air neighbors of Judy Garland and two of her children, Lorna and Joey Luft, during the early 1960s. Lorna Luft states in her memoir Me and My Shadows that Leachman was "the kind of mom I'd only seen on TV." Knowing of the turmoil at the Garland home but never mentioning it, Leachman prepared meals for Judy's children and made them feel welcome whenever they needed a place to stay.

Leachman was a friend of Marlon Brando, whom she met while studying under Elia Kazan in the 1950s. She introduced him to her husband, who became close to Brando as well, directing him in The Ugly American and writing a memoir about their friendship called Marlon Brando: The Way It's Never Been Done Before (2005).

Leachman posed "au naturel" on the cover of "Alternative Medicine Digest" (issue 15, 1997) body-painted with images of fruit. This was a parody of the famous Demi MooreVanity Fair magazine cover photo. A vegetarian, she also posed clad only in lettuce for a 2009 PETA advertisement.

Leachman's autobiography Cloris: My Autobiography was published in March 2009. She wrote the bestselling book with her former husband, George Englund.