Clooney was born in Maysville, Kentucky, to Andrew Joseph Clooney and Frances Marie Guilfoyle, both of whom were Roman Catholics of Irish and German ancestry. Her father was an alcoholic and she and her brother and sister were constantly moving back and forth between her parents. When Rosemary was fifteen, her mother and brother, Nick, moved to California. She and her sister, Betty, remained with their father.

Rosemary, Betty, and brother, Nick, all became entertainers. In the next generation, some of her own children, including Miguel and Rafael, and her nephew, George Clooney, also became respected 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 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 — despite the fact that Clooney hated the song passionately. She had been told by Columbia to record the song, and that she would be in violation of her contract if she did not do so.

Around 1952, Rosemary recorded several duets with Marlene Dietrich.

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 1960 she and Crosby co-starred in a 20-minute CBS radio show that went to air before the midday news every weekday.

In 1956, she starred in a half hour syndicated television musical variety show The Rosemary Clooney Show. The show featured The Hi-Lo's singing group and Nelson Riddle's orchestra. The following year, the show moved to NBC prime time as The Lux Show Starring Rosemary Clooney but only lasted one season. The new show featured the The Modernaires singing group and Frank DeVol's orchestra.

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. In 1964 she went to Reprise Records, and in 1965 to Dot Records. In 1966 she went to United Artists Records.

Beginning in 1977, she recorded an album a year for Concord Records, which continued until her death. This made her something of an anomaly, because most of her generation of singers had long since stopped recording regularly by then.

In the late-1970s and early-1980s, Clooney was also a pitch-person for Coronet paper towels, for which she sang a memorable jingle that goes, "Extra value is what you get, when you buy Coro-net." Jim Belushi later parodied Clooney and the commercial while as a cast member for NBC's Saturday Night Live in the early 1980s. She sang a duet with Wild Man Fischer on "It's a Hard Business" in 1986.

In 1994, Clooney guest starred in the NBC medical drama ER (starring her nephew George), for which she was nominated for an Emmy Award.

In 1999, Clooney founded the Rosemary Clooney Music Festival, held annually in her hometown of Maysville, Kentucky. She performed at the festival every year until her death. Proceeds benefit the restoration of the Russell Theatre in Maysville, where Clooney's first film, The Stars are Singing, premiered in 1953.