The Melbourne-born actress - whose television credits include Brothers & Sisters and Six Feet Under - will play New Idea editor Dulcie Boling in The ABC's account of the Australian 'magazine wars' of the 1980s and 1990s.
Mandy McElhinney, who most recently made a cameo in satirical political comedy At Home with Julia, will star opposite Griffiths as Woman's Day editor Nene King.
McElhinney is also known to Australian audiences for her role as Rhonda in insurer AAMI's 'safe driver' campaign.
"We're very excited to have Rachel and Mandy playing these formidable women, Dulcie Boling and Nene King," producer Mimi Butler said in a statement.
"It's been a dream story to work on, the drama's all there - it's quite Shakespearian. Set in the kingdoms of Packer and Murdoch; there's rivalry and rebellion, love and tragedy, and great victories along the way - all taking place amid the decadence and rock and roll of the '80s and '90s."
Rob Carlton, who appeared in the original Paper Giants, will return as media mogul Kerry Packer.
Paper Giants: Magazine Wars will be produced by Southern Star. Filming on the drama gets underway in Melbourne on August 13.
Watch a TV spot for Paper Giants: The Birth of Cleo below: