In 2004, she took on her first lead role as Sadie Harrison in the CTV teen drama Instant Star. Starting in 2007, she had a recurring role as Kara Zor-El (aka Supergirl) in The CW serial drama Smallville. This opened the door for Vandervoort to become a genre TV darling, with roles in the Syfy film Riverworld, guest appearances on the series Haven,and a starring role as Lisa in the 2009 ABC revival of the science fiction series V. From 2014 to 2016,Vandervoort starred in the Space supernatural series Bitten, a TV adaption of Kelley Armstrong's book series Women of the Otherworld as Elena Michaels. In 2016, she returned to DC television, taking on the role of Brainiac 8 in Supergirl, starring Melissa Benoist.
She has also appeared in several features, including This Means War (2012) alongside Chris Pine and Tom Hardy, Ted (2012) with Mark Whalberg and Seth MacFarlane, and the horror film Jigsaw (2017). Next up, she is set to appear in the Jen and Sylvia Soska remake of Rabid (1977), originally directed by David Cronenberg.