The metal rocker and his actress partner will play the roles in the sexploitation slasher movie, directed by Adam Bhala Lough and produced by Edward R. Pressman and David Gordon Green.
Commenting on Manson's casting in the film, Green said he was excited about where the project would take the horror genre, Variety report.
Unveiling details of 'Splatter Sisters' at the Cannes Film Festival, Green said: "This is a role Marilyn Manson was born to play, and with Evan Rachel Wood bringing dramatic gravity to the ensemble, I have No Doubt this will take the horror genre to a new level."
Pressman added: "Lough's unique talent and energy will make 'Splatter Sisters' a very special and markedly commercial film.
"I've always been attracted to smart movies about killers made by directors with a real vision."