In the mid-1990s Karnes was a company member with the Oregon Shakespeare Festival, playing major roles in such plays as Love's Labours Lost and Tom Stoppard's Arcadia. Karnes also starred in the films The Joyriders (1999) and The Next Best Thing (2000).
From 2002 to 2008 Karnes played the role of Detective Holland "Dutch" Wagenbach on The Shield.
In 2008, Karnes played the recurring role of ATF Agent Josh Kohn on FX Network's series Sons of Anarchy, created by writer/actor Kurt Sutter of The Shield. Karnes was an antagonist to SAMCRO vice President Jax Teller and his sometime girlfriend Tara Knowles. That same year he also appeared in the films Chasing 3000 and Broken Angel.
From 2009 to 2010 Karnes had a recurring role on Burn Notice as Tyler Brennan, a sinister gunrunner with a predilection for kidnapping relatives of those he wishes to leverage.
In 2011 Karnes appeared in Body of Proof episode "Hunting Party". In 2012 he played Secretary of Defense william Curry in a recurring role on ABC's Last Resort. In 2013 Karnes also appeared in the pilot episode of Jeff Eastin's drama series Graceland as Supervising Agent Gerry Silvo. In 2014 Karnes also appeared in FOX's series, Gang Related, as Agent Carter of IAD, as well as in the film Jayhawkers as the chancellor of the University of Kansas.
