In 1992 she won Ford Models' Supermodel of the World contest. Helfer retired from fashion modelling in 2002 and claimed all her shoots since then are related to projects or product endorsements. She has appeared in ad campaigns for Ralph Lauren, Versace, Chanel, and Giorgio Armani.
Helfer relocated to Los Angeles in 2002 to pursue a full-time acting career. Her first acting assignment was a co-starring role as Sarah on the television series Jeremiah. She later played a model named Ashleigh James on the May 16, 2002, episode of CSI: Crime Scene Investigation ("The Hunger Artist"). In 2002, she played "Eva" in the independent film White Rush.
Helfer has walked for top fashion shows, such as Carolina Herrera, Christian Dior, Claude Montana, Givenchy, John Galliano, and Dolce & Gabbana. Helfer has appeared on the covers of Flare, Amica, ELLE, Cosmopolitan, Marie Claire, and Vogue, among others. She also regularly appeared in photo shoots by Maxim magazine, was the magazine's wall calendar girl for 2005, and was ranked #57 on the Maxim's Hot 100 Women of 2007. Helfer was also featured as the cover model for the February 2007 issue of Playboy.
In October 2006, it was announced that Helfer would not return to host the second season of Canada's Next Top Model so she could concentrate on Battlestar Galactica. Helfer also played a major role in Electronic Arts Command & Conquer 3: Tiberium Wars, as the high-level Nod general Kilian Qatar, along with her Battlestar Galactica co-star, Actress Grace Park. She also starred in the episode "Roadkill" on the second season of Supernatural.
In August 2008 Helfer appeared on the stage of NVISION 08, an event sponsored by NVIDIA, where she discussed her role in Battlestar Galactica as well as the use of computer graphics on the show. Helfer appeared as Chuck’s Season 2 secret agent "handler" in the NBC series Chuck, and as Michael Westen's Season 2 nemesis in the USA Network series Burn Notice as "Carla". She appears as herself in Old 97's music video for their song, "Dance with Me".
She guest starred in "Resonance", the second episode of Warehouse 13 as FBI Agent Bonnie Belski on Syfy. She made a guest appearance in the pilot episode of Fox's 2009 mid-season series Human Target. She has played several prominent video game roles in recent years; including Kilian Quatar in Command & Conquer 3: Tiberium Wars, Veronica Dare in Halo 3: ODST and EDI, the ship-borne artificial intelligence aboard the Normandy SR-2 in Mass Effect 2 and Mass Effect 3. She voices Sarah Kerrigan in StarCraft II: Wings of Liberty as well as the expansion sets Starcraft II: Heart of the Swarm and Starcraft II: Legacy of the Void. Helfer voices the Black Cat in The Spectacular Spider-Man and she reprises the role in Spider-Man: Web of Shadows and Ultimate Spider-Man.
Helfer joined the cast of Jerry Bruckheimer's TNT drama, Dark Blue, as FBI Special Agent Alex Rice. The show was cancelled in November 2010 because of its very low ratings. In October 2010 she made a guest appearance on Lie to Me.
In 2011 she starred in The Black Keys' music video for "Howlin' for You". She made guest appearances in No Ordinary Family (2011), and Franklin & Bash (2011). In 2011, Helfer starred as Morgana, a necromancer, in the TV series pilot 17th Precinct from Ron Moore with Galactica's co-stars James Callis and Jamie Bamber. In October 2011 she got the lead role in the TV Pilot Scent of the Missing as Susannah, a K-9 Search and Rescue Volunteer. In November 2011, she appeared in the Hallmark TV movie Mistletoe Over Manhattan. For 2012, she signed for the recurring role of Alex Clark in the new NBC TV Series The Firm. On May 16, 2012, she appeared in the two-part finale of season 7 of the CBS series Criminal Minds, in which she led a team of bank-robbing serial killers. She guest starred in the second season of the Jane Espenson scripted romantic comedy web series, Husbands.
She co-founded the charity web site "Acting Outlaws" with former Battlestar Galactica co-star Katee Sackhoff, which is open for donations for different causes and charity events. She is also involved in various causes, from animal rescue to the oil spill in the Gulf of Mexico. In 2014, she appeared in a PETA video campaign, encouraging cat owners to keep their pets indoors.
In 2015, she appeared in the series finale of Falling Skies as the Espheni Queen, the leader of the alien race that had invaded Earth and devastated humanity. She also played Louise, a woman attending a doll convention, in the web series Con Man.
In 2016, Helfer was added to the main cast for Season 2 of the Fox TV series Lucifer, playing the lead character's mother who is also the exiled wife of God.
She was married to Jonathan Marshall, a Lawyer whom she met at a mutual friend's birthday party. They separated in May 2017 and Helfer filed for divorce in January 2018.
