Savage was "a popular World War II pin-up model, an Esquire centerfold shot by George Hurrell [and] a tireless barnstorming seller of War Bonds on two tours". She was briefly married to Clark Tennesen between 1939 and 1941, before marrying her agent (and the Max Reinhardt school manager) Burt (or Bert) D'Armand c. 1942–45. The two lived in New York from the late 1950s until his sudden death in 1969.

Although Columbia typically groomed its girls in the mould of Rita Hayworth, Savage's look echoed Ann Sheridan, although her customary blonde locks were reddened for Footlight Glamour (1943) "so that the star, Penny Singleton, would be the only blonde on screen." She joined Joan Davis and Jinx Falkenberg in Two Senoritas from Chicago (1943), and starred (as a brunette) in the first of several outings with Tom Neal in Klondike Kate (1943).

Although Savage and Neal did not see eye-to-eye (she found him "childlike") the duo would star together in Two Man Submarine and The Unwritten Code (both 1944), before their most famous film, the 1945 film noir Detour. Reminiscing in the 1980s about her career as a stalwart B movie Actress, Savage dismissed most of her roles as "mindless", saying: "The actresses were just scenery. The stories all revolved around the male actors; they really had the choice roles. All the actresses had to do was to look lovely, since the dialogue was ridiculous". Detour, she felt, was different. The two leads underwent role Reversal, with Savage's Vera blackmailing Neal's Al, in a style described by her manager Kent Adamson as "vicious and predatory… very sexually aggressive".

Savage eventually started appearing in commercials and industry films before essentially withdrawing from acting in the mid-1950s.

She attended 64th Street Grammar School, and Mount Vernon Junior High, and "first stepped on a soundstage at the age of 17" at MGM Studios, screen tested by Edgar Selwyn, "Ann spent time among the more famous Hollywood kids of the day like Lana Turner, Judy Garland, Freddie Bartholomew and Deanna Durbin." Her MGM-test did not work out, prompting her to "get her teeth capped" and "[a]cquir[e] theatre training at the Max Reinhardt workshop" on Sunset Boulevard. Reinhardt oversaw her name-change, and Bernice became Ann Savage. The Reinhardt school's manager, Bert D'Armand, would also become Savage's agent, and the two would later marry. Savage was offered a screen test by Fox, but she "decided not to turn up as she knew the studio already had a bevy of pretty blondes".

After her husband's death, Savage returned to Los Angeles to be near her mother, and "took odd jobs to Finance flying lessons," becoming a licensed pilot in 1979. Her manager quoted her as saying that she "loved flying because it put her 'closer to God and Bert'." She also became "part-owner of a small tool company," and later "took a secretarial course" and became "a docket clerk receptionist and then a secretary at the law firm [Loeb & Loeb] in Los Angeles."

When Detour entered the public domain, it was frequently syndicated on television channels, and released in numerous VHS incarnations. Gaining cult status and garnering critical acclaim as "arguably film noir's greatest low-budget feature", this exposure earned Savage a new, younger, following. From the 1980s, Savage also attended a number of film festivals, helping to bolster her personal status, and leading her to emerge once more as "a glamorous figure-about-Hollywood at film festivals and galas".

In 1983, she attended a screening of Detour held as a tribute to Director Edgar Ulmer and met up there with Ulmer's widow, Shirley.

Savage's exposure and the praise heaped on Detour led to her appearing in the 1986 film Fire with Fire and in a guest role on the television show Saved by the Bell.

In 2005, Savage was elevated to the status of "icon and legend" by the Academy of Motion Picture Arts and Sciences. In 2007, TIME magazine named Savage's role as Vera in Detour one of the "Top 10 Movie Villains", and Detour itself as one of the hundred best movies. In 2010, McFarland and Co. published Savage Detours: The Life and Work of Ann Savage, by Kent Adamson and Lisa Morton.

In 2007, she "enjoyed a comeback", and rave reviews when Canadian filmmaker Guy Maddin cast her as his mother in his "personal portrait of his hometown", My Winnipeg (2008). Maddin, according to Savage's manager, is a fan of Detour, while Savage's role in his film—"a part that had been tipped to bring her an Academy Award"—also "introduced her to a legion of new fans, including Steven Spielberg, John Travolta and Martin Scorsese". Maddin has stated that he cast Savage because she "would have scared the pants off Bette Davis". My Winnipeg was critically acclaimed and won prizes from both the Toronto Film Critics Association and the San Francisco Film Critics Circle, as well as the Best Canadian Feature Film at the Toronto International Film Festival and a Genie Award nomination.

Remaining blonde "throughout her eighties", and continuing to attend "film festivals and galas", Savage had a series of strokes and became a resident of the Motion Picture & Television Country House and Hospital in California. She died in her sleep on December 25, 2008, aged 87. Her cremated remains were interred with beloved husband D'Armand at the Hollywood Forever Cemetery (in Los Angeles, California). Her "personal and career memorabilia" will become part of the Harry Ransom Center at The University of Texas at Austin, alongside the archives of Robert De Niro, David Mamet, David O. Selznick and Gloria Swanson (among others).

Savage instead made a screen test with Columbia Pictures — after playing Lorna in a Reinhardt acting showcase of Odet's Golden Boy" — and was offered a contract. Recalling Columbia mogul Harry Cohn as "a friendly Uncle type", Savage remembered Cohn being intimidated by acid-tongued Rosalind Russell. The two actresses featured together in What a Woman!, one of a dozen films with Savage to be released in 1943.