The actor will play a suspected serial rapist in the veteran crime drama's 150th episode, according to TV Line.
His character will stalk a terrified woman (Dina Meyer) while managing to evade justice.
"[Dina] plays a victim and believes [Jay's character] is the predator," confirmed executive producer Erica Messer. "But only our team knows the truth."
Karnes previously played detective Dutch Wagenbach on FX cop drama The Shield and has recently appeared in episodes of Body of Proof and Burn Notice.
His Criminal Minds guest stint will air in early 2012.
Scrubs actress Bellamy Young and Alien 3's Charles S Dutton have both signed up for roles in forthcoming Minds episode 'The Bittersweet Science', due to air on November 30.
The series continues on Wednesdays at 9/8c on CBS.
> Criminal Minds Paget Brewster rules out Prentiss, Hotch romance
Watch a promo for the next Criminal Minds - featuring guest star Jack Coleman - below: