The actor - who played Chuck on Supernatural - will play a professor on the CBS crime procedural, Entertainment Weekly reports.
Benedict's character Paul Friedman will cross paths with Patrick Jane (Simon Baker) and the CBI team when a student is murdered in his lab.
In addition to his Supernatural role, 42-year-old Benedict has recently appeared on Touch, Psych and NCIS: Los Angeles.He also played a recurring role on Keri Russell drama Felicity between 1998 and 2002.
His Mentalist episode - titled 'Red in Tooth and Claw' - will air on CBS in February.
The series will return to US screens on January 6. In the UK, The Mentalist airs on Fridays at 9pm on Channel 5 in the UK.
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Watch a clip from The Mentalist below: