She was born in Maysville, Kentucky, about 60 miles up the Ohio River from Cincinnati, Ohio to Andrew Joseph Clooney and Frances Marie Guilfoyle, both of whom were of Irish descent (Rosemary's paternal great-grandparents, Nicholas Clooney and Bridget Byron, were born in Ireland), although Clooney's paternal grandmother, Crescentia Koch, was German. Her father was an alcoholic and she and her brother and sister were constantly moving back and forth between her parents. Eventually, when Rosemary was 13, she and her sister Betty went to live with their mother and her brother Nick went with their father.

Rosemary, Betty, and brother, Nick, as well as her nephew, George Clooney (Nick's son), all became entertainers. In 1945 the Clooney sisters won a spot on Cincinnati's radio station WLW as singers. Her sister Betty sang in a duo with Rosemary for much of her early career.

Clooney's first recordings, in May of 1946 were for Columbia Records as a singer with the big band of Tony Pastor. She continued working with the Pastor band until 1949, making her last recording with the band in May of that year and her first as a solo artist a month later, still for Columbia. In 1951 her record of "Come On-a My House" became a hit, her first of many singles to hit the charts.

In 1954 she, along with Bing Crosby, Danny Kaye, and Vera-Ellen, starred in the movie White Christmas. In later years, Clooney would often appear with Crosby on television, such as in the 1957 special The Edsel Show, and the two friends made a concert tour of Ireland together. Crosby opined that Clooney was "the best in the business."

In 1958, Clooney left Columbia, doing a number of recordings for MGM Records and then some for Coral Records. Finally, toward the end of 1958, she signed with RCA Victor Records, where she stayed until 1963 except for doing some recordings in 1960 for Reprise Records. In 1964 she went to Reprise again, shifting the next year to Dot Records. In 1966 she went to United Artists Records. In 1986 she sang a duet with Wild Man Fischer on "It's a Hard Business".

In 1968, Clooney was present at the assassination of Robert F. Kennedy, with whom she was a close friend. The event traumatized her life for years afterward. She had a nervous breakdown and serious drug problems. Many attribute some of Clooney's extraordinary abilities to her being affected by bipolar disorder, commonly known as manic depression.

Rosemary Clooney was married three times, twice to José Ferrer (from 1953 until 1961 and then again from 1964 to 1967) by whom she had five children, including actor Miguel Ferrer, born in 1955, and Gabriel Ferrer, born 1956, who married Debby Boone, and once to Dante DePaolo (whom she married in 1997).

A lifelong smoker, Rosemary Clooney was diagnosed with lung cancer at the end of 2001 and despite surgery died six months later. Her nephew George served as a pallbearer at her funeral, which was attended by numerous stars including Al Pacino.