The film is set to be directed by The Best Exotic Marigold Hotel's John Madden with Theron also serving as co-producer, reports Deadline.
Murder Mystery is an "affectionate deconstruction" of an Agatha Christie story about an American couple abroad. The project plans to start production in 2013.
Theron can be currently seen in two summer films, Snow White and the Huntsman and Ridley Scott's sci-fi Prometheus.
On dressing up for red carpet events, Theron recently said: "I think you have to kind of not try to be trendy and just really do what feels comfortable because, there's nothing worse than someone wearing something because someone told them to wear it and they feel uncomfortable in it.
"I feel really fortunate that I work with really talented people in the industry, so there's always amazing stuff, but at the end of the day, I have to be able to put it on and feel like me."
Watch Digital Spy's interview with Charlize Theron at the Prometheus premiere below: