The actor - known for playing Desmond Hume on ABC's island-set drama - has been cast as a multi-millionaire playboy, Deadline reports.
Cusick will appear in three episodes of the CBS crime series as Tommy Volker, who becomes a suspect in the murder of a television reporter.
The 45-year-old star recently appeared on Scandal as a series regular but will not return to the show for its second season.
Cusick also made a guest appearance in the fourth season of Fox's Fringe, while his former Lost co-star Daniel Dae Kim has revealed that the pair have discussed an on-screen reunion on Hawaii Five-0.
English actress Polly Walker (Prisoners' Wives) has also been confirmed to appear in the fifth season of The Mentalist.
The series returns to CBS on September 30. In the UK, The Mentalist airs on Channel 5.
> TV's Greatest Rivalries: Friday Fiver
Watch a promo for the new season of The Mentalist below: