Karpluk began her acting career in Vancouver and between 2000 and 2005, she appeared in more than a dozen television movies and series before landing the role of Kate in Godiva's. Her work during this period included "Voice of Sylan" in the final episode of Dark Angel and the TV movie Family Sins. She was also in a short-lived US television series called Glory Days in 2002. In 2004, she appeared in Legend of Earthsea and played a serial killer in Ripper 2: Letter from Within. She earned a Leo nomination for her first season of Godiva's and a 2006 Gemini nomination for Best Performance by an Actress in a Continuing Leading Dramatic Role. Since Godiva's, Karpluk has continued to work in television and short films. In 2007 she appeared in Bionic Woman, Flash Gordon, and The L Word. She had a leading role in a 2008 television movie, Smokejumpers, directed by John Terlesky.

Karpluk was offered the lead role of Erica Strange in the CBC Television series Being Erica when she was working in Los Angeles on The L Word. In 2009, Karpluk won the Gemini award for Best Performance by an Actress in a Continuing Leading Dramatic Role for her portrayal of the titular character. She also had a recurring role as Alice the radio station manager during the first season of The CW's Life Unexpected. Her only appearance in the second season was in the series finale because of a scheduling conflict resulting from Being Erica being picked up for a third year. Karpluk has also had recurring roles on Rookie Blue and Slasher, and starred in the web series Riftworld.