In 2003, she played Number Six on Battlestar Galactica. In 2004, she portrayed Farrah Fawcett in the telefilm 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. She appeared in Spiral and The Green Chain later the same year.
In 2003, the television series Battlestar Galactica was used as the basis for a 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 TV series, which completed its fourth and final season on March 20, 2009. Due to the special nature of the Number Six character – there are many "copies" of Number Six with distinct personalities – Helfer has, in effect, played numerous roles on the series. In 2009, she reprised her role as Number Six in Battlestar Galactica: The Plan – a television movie that tells the story of the series from the Cylons' point of view. In 2012, she voiced a prototype Cylon in the prequel Battlestar Galactica: Blood & Chrome.
In 2003, Helfer married 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, citing irreconcilable differences. The divorce was settled in 2019.