In 1992, she won Ford Models' Supermodel of the World Contest and was subsequently signed to the Elite Model Management and is currently signed with Trump Model Management. She has appeared in ad campaigns, including Ralph Lauren, Chanel, and Giorgio Armani. Helfer has walked for top fashion shows such as Carolina Herrera, Christian Dior, Claude Montana, Givenchy, John Galliano, and Dolce & Gabbana. Helfer has graced 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.[1] She also posed topless, but not entirely nude, for the February 2007 issue of Playboy.

While working in New York as a model, Helfer hosted a Canadian television fashion program Ooh La La. She relocated to Los Angeles in 2002 to pursue a full-time film career. Her first acting assignment was a co-starring role as Sarah on the television series Jeremiah. Thereafter she played the role of a model, Ashleigh James, in the May 16, 2002 episode "The Hunger Artist" on CSI: Crime Scene Investigation. In 2002, Helfer played the female lead, Eva, in the independent film White Rush. In 2003, Helfer was chosen to play Number Six on Battlestar Galactica (see section below).

In the fall of 2003, Helfer was offered the role depicting Farrah Fawcett in the NBC telemovie Behind the Camera: The Unauthorized Story of 'Charlie's Angels'. Concurrent with her role in Battlestar Galactica, Helfer began producing and hosting Canada's Next Top Model on May 31, 2006. In 2006, Helfer appeared in the motion pictures Spiral and The Green Chain.

In October 2006, it was announced that Helfer would not return to host the second season of Canada's Next Top Model in order to concentrate on her work on Battlestar Galactica.[2] Helfer also played a major role in Electronic Arts Command & Conquer 3: Tiberium Wars, as a character named "Kilian Qatar", along with her Battlestar Galactica co-star, Grace Park.[3] She also starred in the episode "Roadkill" on the second season of the American paranormal drama TV series Supernatural.

In 2003, the television series Battlestar Galactica was used as the basis for a new three hour miniseries on the Sci Fi channel. The project was written and produced by Ronald D. Moore and directed by Michael Rymer. Helfer played the role of Number Six, a humanoid Cylon operative. She continued that role as a regular cast member in the subsequent series, which entered its fourth and final season in 2008.