Helen Merrill was born Jelena Ana Milčetić on July 21, 1929, in New York City, the daughter of Croatian immigrants Frano and Antonija Marija Milčetić, who came from the island of Krk. She began singing in Bronx jazz clubs in 1944, at fourteen, and was working in music full time by sixteen. According to AllMusic she sang with the Reggie Childs Orchestra in 1946 and 1947, and in those years, while married to the clarinetist Aaron Sachs (1948 to 1956), she sat in with Charlie Parker, Miles Davis and Bud Powell. Her son, born in 1951, grew up to be the singer and songwriter Alan Merrill. Her first record came in 1952, when she sang "A Cigarette for Company" with Earl Hines's band on the D'Oro label, a session on which Etta Jones also sang.

Mercury signed her to its EmArcy jazz label, and on December 22 and 23, 1954, she recorded the album Helen Merrill with the trumpeter Clifford Brown in arrangements by Quincy Jones, then 21. Brown had made a comparable album with Sarah Vaughan only days earlier. The band included the pianist Jimmy Jones, the guitarist Barry Galbraith, the bassists Milt Hinton and Oscar Pettiford, and the multi-reed player Danny Bank. The seven standards, among them "Don't Explain" and "You'd Be So Nice to Come Home To," made the record an immediate success and led Mercury to extend her contract by four albums. Helen Merrill with Strings (recorded October 1955, arranged by Richard Hayman, with Hank Jones at the piano) followed, and then Dream of You, recorded June 26, 27 and 29, 1956, with arrangements and conducting by Gil Evans. It came just before his Miles Ahead with Miles Davis and, by AllMusic's account, helped bring Evans out of retirement. Merrill at Midnight (1957, arranged by Hal Mooney, with Marian McPartland on piano for four tracks) and The Nearness of You (1958) completed the EmArcy run. In 1959 she made You've Got a Date with the Blues for MetroJazz, with Kenny Dorham on two tracks, and American Country Songs for Atco.

From about 1959 she spent much of her time in Europe, where she found a larger audience than at home. In Stockholm she sang with the pianist Jan Johansson at the Nalen club, and in Italy she worked with the composer and bandleader Piero Umiliani, the drummer Romano Mussolini, Chet Baker and Stan Getz. Her Italian recordings include Parole e Musica (RCA Italiana, 1960), made with Umiliani's ensemble, on which each song is preceded by a spoken Italian version of its lyric, and an EP of Italian songs arranged by Ennio Morricone. On October 2, 1960, she recorded the Cetra EP Jazz in Italy N.8 in Milan with the drummer Franco Tonani, the bassist Giorgio Azzolini, the tenor saxophonist Gianni Basso, the trombonist Dino Piana and the pianist Renato Sellani. She was also in Tokyo in February 1963, recording Helen Merrill in Tokyo for King Records with Takeshi Inomata and his West Liners, with Norio Maeda arranging and Jiro Inagaki on tenor saxophone and flute.

Back in the United States in the mid-1960s she made The Artistry of Helen Merrill (Mainstream, 1965) and began a partnership with the pianist and arranger Dick Katz that produced two Milestone albums: The Feeling Is Mutual (1967), with Thad Jones, Jim Hall and Ron Carter, and A Shade of Difference (1969, recorded July 1968). In 1966 she moved to Japan, and in April 1967 she married Donald J. Brydon, the Tokyo-based Asia bureau chief of United Press International. Over the next several years she made a run of albums for Victor in Japan, among them Autumn Love (1967), Helen Sings, Teddy Swings (1970) with Teddy Wilson, and Sposin' (recorded October 1971) with Gary Peacock, Masahiko Satoh and the drummer Motohiko Hino. She also produced albums for Trio Records and co-hosted a radio show with Bud Widom on the American Forces network in Tokyo, and she built a following in Japan that remained strong decades later. She returned to the United States in 1972.

Her later records were made on both sides of the Atlantic. John Lewis / Helen Merrill (1977) paired her with the pianist John Lewis, with Hubert Laws on flute and Connie Kay on drums for three tracks. Chasin' the Bird (Inner City, 1980) used Katz's arrangements and a band with Pepper Adams, the bassist Rufus Reid and Mel Lewis. In Paris she recorded No Tears, No Goodbyes (1984) with the pianist Gordon Beck and Music Makers (1986) with Steve Lacy and Stéphane Grappelli. In August 1987 she and Evans re-recorded the Dream of You repertoire as Collaboration, the best received of her 1980s albums. She also sang on two tracks of Billy Eckstine's last album, Billy Eckstine Sings with Benny Carter (recorded November 1986), and co-produced it. The 1989 EmArcy albums Duets, a bass-and-voice record with Ron Carter, and Just Friends, with Getz, led to Clear Out of This World (1991), with Wayne Shorter, Tom Harrell and Roger Kellaway. Brownie: Homage to Clifford Brown (recorded January 1994, Verve) honored her first great collaborator. She followed it with You and the Night and the Music (1997), with Charlie Haden and Paul Motian, then Jelena Ana Milčetić a.k.a. Helen Merrill (2000), which includes traditional Croatian songs sung in Croatian, and Lilac Wine (2003).

Her third husband was the arranger and conductor Torrie Zito, who arranged and conducted for her on many of those recordings; the marriage lasted until his death in 2009. Her son Alan Merrill, who wrote and first recorded "I Love Rock 'n' Roll" as lead vocalist of the band Arrows, died in 2020. Lilac Wine is the most recent studio album in her discography, and her early EmArcy records have stayed in circulation through repeated reissues, including Analogue Productions vinyl editions of Helen Merrill in 2020 and 2023.

Merrill has a warm, expressive voice and is at her best on slow and medium-tempo standards, where she shades a lyric closely and takes chances with phrasing. The AllMusic critic Scott Yanow wrote that her infrequent records tend to be special, with surprises and risk-taking, and AllMusic files her under vocal jazz, standards, cool and post-bop. The 1954 session with Clifford Brown and Quincy Jones is essentially straight-ahead bop, while the Gil Evans albums of 1956 and 1987 set her in slow, spacious orchestral writing that foreshadowed his work with Miles Davis. She chose collaborators across styles, from Brown and Evans to the modern-jazz pianists and bassists of the Katz and Ron Carter dates, and later the open rhythm section of Haden and Motian. The critic Will Friedwald judged that she improved with age and that her albums of the 1990s and 2000s were a marked improvement on her early work. Her years in Italy and Japan kept her largely out of American view for a long stretch, but the 1980s and 1990s recordings for EmArcy, JVC and Verve, and her American performances, revived her profile.