Kwanten began acting on the television shows A Country Practice, Hey Dad..! and Spellbinder. In 1997, he joined the cast of the Australian soap opera Home and Away, playing lifeguard Vinnie Patterson. He eventually chose to leave the series in 2002, shortly after his character married and became a father. Kwanten had previously guest starred on the serial as Robbie Taylor in 1994. Moving to the United States, Kwanten was cast as Jay Robertson in Summerland (2004–05). He appeared in the films Flicka (2006), with Maria Bello, Alison Lohman, and Tim McGraw, and Dead Silence (2007), a horror film in which he played the leading role, Jamie Ashen.

Kwanten played the role of Jason Stackhouse in the HBO series True Blood, based on Charlaine Harris’ The Southern Vampire Mysteries series of novels, which aired from 2008 until 2014. He stars in the psychological thriller Red Hill, which was directed by Patrick Hughes. He won a lead role in the Joe Lynch comedy-horror film Knights of Badassdom along with Steve Zahn, Summer Glau and Peter Dinklage. In October 2010, it was announced that Kwanten will play Charles Manson in an upcoming, yet-to-be-titled biopic, to be directed by Brad Anderson. In 2012, he appeared in MysteryGuitarMan’s video “Dual Action”. In 2013, Kwanten played Marvel character “Venom” in the short film Truth in Journalism and portrayed Conall in the 2014 action adventure film Northmen: A Viking Saga.

In 2015, Kwanten voiced the role of Blinky Bill, a Koala in Blinky Bill the Movie based on the iconic children’s book by Dorothy Wall.