But her good friend, Family Guy creator Seth MacFarlane, was eager to showcase the actress's comic side.
The pair team up in the comedy A Million Ways to Die in the West, out May 30.
"The most flattering thing you could say to me is that I could be a match to him," Theron, 38, tells PEOPLE in this week's issue. "I am a huge fan and have been for many, many years."
"He's definitely the kind of person that from afar fascinates me. Then you have this opportunity to know someone, and when they don't let you down, that's such a gift. The thing you remember when you're 80 and lying on your deathbed is that. I'll remember the friendship and working with Seth on this movie."
MacFarlane, 40, says of their bond, "We had said 'Hi' here and there. But it was so quickly into the process, I felt like she was someone I'd been working with my entire life. I really felt like I made a lifelong friend."
Reporting by JULIE JORDAN
For more from the stars of summer's biggest blockbusters, pick up this week's issue of PEOPLE magazine