Living in New York City, Helm began her pursuit of an acting career, which eventually led to Hollywood. Beginning in the 1950s, she made guest appearances on different television series and made her motion picture debut in 1960.
Helm was cast as Linda Moon in the 1960 episode "A Thief or Two" on CBS's anthology series, The DuPont Show with June Allyson, with co-star Lew Ayres. She appeared on the CBS western series Rawhide in the episodes "Incident Near Gloomy River (1961) and "Inside Man" (1962). She guest-starred in an episode of the CBS sitcom My Sister Eileen, with Elaine Stritch and Shirley Bonne.
In 1961, she guest-starred in the premiere episode of ABC's Bus Stop drama series with Marilyn Maxwell, a one-season drama set about a bus station/diner in fictitious Sunrise, Colorado. That same year, she appeared in the first season of CBS's Route 66 in the episode "The Clover Throne", and in the syndicated crime drama The Brothers Brannagan in the episode "Equinox." She also played Glamis Barlow, the title character, in the Perry Mason TV episode, "The Case of the Duplicate Daughter."
Helm drew national recognition as the love interest of Elvis Presley in his 1962 film Follow That Dream. She made five more films during the 1960s including The Iron Maiden (released in the US as Swinging Maiden), a 1962 British made comedy film, The Interns (1962), Honeymoon Hotel (1964), The Unkissed Bride (1966), and the horror film Nightmare in Wax (1969).
Helm made three appearances on Wagon Train, an American Western series that ran on NBC from 1957–62 and then on ABC 1962–65. The first episode Helm was on was entitled "The Dick Pederson Story" (10 Jan. 1962); the second episode was entitled "Heather and Hamish" (10 Apr. 1963) and the third was "The Story of Cain" (16 Dec. 1963).
On January 15, 1963, Helm guest-starred in the episode "Protective Custody" of NBC's Laramie western series. David Brian played Walt Douglas, an official of the stage line, who arrives in Laramie seeking his estranged daughter, Alicia, portrayed by Helm. Series character Jess Harper (Robert Fuller) knows Alicia as a saloon hostess using the name Leona. Alicia is involved with two outlaws, Cass and Willard, played by Ron Hayes and Gregory Walcott, respectively, who aim to steal a mining payroll. Series character Slim Sherman (John Smith) tries to bring about reconciliation between Walt and Alicia, but Alicia shoots her father. Slim keeps the wounded Walt and Alicia at his relay station pending a hearing while Cass and Willard plan to seize the payroll when it is dropped off at the relay station.
She was also "Helena Dales" on the Gunsmoke episode "One Killer on Ice."
Later in 1963, she was cast as Joanie in the series finale, "The Convention," of the modern western series, Empire, with Richard Egan as rancher Jim Redigo, along with other guest stars Diane Brewster, Alan Hale, Jr., and L.Q. Jones.
She appeared in The Magic Sword opposite Basil Rathbone and Gary Lockwood. She was originally cast to play Joan Crawford's daughter Carol in William Castle's Strait-Jacket but was replaced by Diane Baker.
In 1965, Helm was cast in the ABC western series The Big Valley, which starred Barbara Stanwyck. Her first appearance was on October 20, 1965 in the first-season episode "Heritage" in the role of Brydie Hanrahan. Helm then returned on March 4, 1968 in the third Season in the episode entitled "The Devil's Masquerade," playing the role of Nancy. Both episodes featured her with cast member Lee Majors prominently in each one.
In 1968, Helm appeared as Irene Park in Season 1 of Hawaii Five-O.
From 1971 to 1973, Helm was a regular cast member on the ABC soap opera General Hospital.
Her brother, Peter Helm, also became an actor. The two appeared separately on the NBC medical drama The Eleventh Hour. Anne Helm starred as Janet Nolan in the 1964 episode "The Only Remaining Copy Is in the British Museum."
After her acting career ended in 1986, Helm published children's books The Sunshine Angel Book for Angel Workers of All Ages (1992) and The Little Angel Workbook for Children of all Ages (1993) as Annie Helm.
Anne Helm was married from 1968 to 1969 to author John Sherlock, with whom she had a son, Peter Sherlock. Her second husband was actor Robert Viharo, whom she wed in 1971 and had a daughter, Serena Viharo (born 1977), who also became an actress. Helm and Viharo divorced in 1979.