According to TV Guide, the Fox News anchor will appear in one episode of the show as a "potential murder suspect".
O'Reilly is friends with Rizzoli & Isles creator Janet Tamaro and the show's star Angie Harmon, who plays Jane Rizzoli.
Speaking about O'Reilly's visit to the set last year, Tamaro said: "He took one look at the autopsy table and said, 'Yeah, a lot of people would like to see me on that'. I said, 'Well, how about you come back and do a guest spot?'"
O'Reilly is expected to film his episode in June.
Chris Vance, Colin Egglesfield and Jacqueline Bisset have already signed up for roles in the second season of Rizzoli & Isles.
The show will return on July 11 at 10/9c on TNT.