The 34-year-old is due to play the new boyfriend of Bridget, the ex-wife of Ashton Kutcher's newly-unveiled character Walden Schmidt.
Arrested Development star Judy Greer will make her first appearance as Bridget on Monday's edition of the CBS sitcom.
The ninth season premiere of Two and a Half Men - the first to air since Charlie Sheen's firing from the show - scored a gigantic 27.8m viewers this week.
Manganiello recently signed on to play a character called Big Dick Richie in male stripper film Magic Mike.
He claimed this week that the True Blood cast like to joke about their frequent nude scenes.
Two and a Half Men continues Monday at 9/8c on CBS.
> Ashton Kutcher's Two and a Half Men debut: Digital Spy's review