As she chats to Living, she now says she now sees the movie as her comeback.
"I had done a couple of movies before this, which were logistically, material-wise and shooting-wise very, very hard and this movie was my comeback movie, where I realised, 'Okay, I really love what I do,'" she says. "I had gotten myself into situations where logistically I was finding it very hard. It was no reflection on the film or the people I was working with ... a lot of it has to do with where you find yourself in life. I was loving the work, but I wasn't enjoying the process so I thought I would take a big break.
"This came at exactly that time and just felt like a great opportunity. Something about Seth, this cast and the material made me think, 'Maybe this is exactly what I wanted to do', and boy was I right.
"I had that much fun on this film. It was a true reminder that when you do it right, it's f***en awesome."
It's one of six times Theron cusses in the course of a 20-minute interview, during which dirty gestures, raw humour and entertaining anecdotes paint the stunning South African-born star as being refreshingly grounded.
Despite her longevity in Tinseltown, there isn't an ounce of Hollywood preciousness about Theron, who is currently dating 53-year-old actor Sean Penn. When it's suggested that perhaps MacFarlane's humour belongs in a boys' club, she raises her eyebrows and laughs. "That's bullsh**. I actually think women are way more crude than guys.
"I've had a couple of moments with Seth where he was like, 'What?'
"So, you're welcome, Seth."
Better known for his adult animated TV series Family Guy and 2012's talking teddy bear hit Ted, MacFarlane has frequently stirred controversy with his "crass" and "derogatory" humour.
It was while MacFarlane was working on Ted 2 with writing partners Alec Sulkin and Wellesley Wild that the trio starting watching old Westerns to kill time. They became "painfully aware what a horrible, depressing place [the wild West] must have been to live, despite how much it has been romanticised in popular culture".
They wrote the story of Albert (played by MacFarlane) - a sheep farmer in 1882 Arizona who is devastated after being rejected in love, then finds his world turned around by the arrival of a mysterious newcomer, Anna (Theron).
The film attracted an impressive cast including Liam Neeson, as Anna's notorious bandit husband Clinch Leatherwood, Neil Patrick Harris, Amanda Seyfried and Giovanni Ribisi, but finding the right person to portray Anna was crucial.
MacFarlane had shared the same agent as Theron for years and had heard she had a fun sense of humour, so thought she might be a good fit.
He was right.
"There's nothing that's more interesting and exciting to me when I'm casting as [when] somebody already comes in with a strong point of view on what they want the role to be.
"The meeting I had with Charlize was just that. She talked about the script in the way that I and my co-writers talked about the script and she understood exactly what the tone was."
In the film, traditional Western gender roles are flipped with Anna being the strong, confident, gunslinger who must save Albert from his insecurities and lack of courage.
MacFarlane, 40, says working with the "alpha woman" was "really hot", but quickly adds how Theron proved to be an incredible asset behind the cameras as he juggled his first major acting role with producing and directing the film.
"She has done this a billion times. She's made all these movies and won an Oscar so for me, not having acted before, it was nice to have the luxury of quietly whispering to her, 'Is this working?' She was a partner in every professional sense ... somebody that I could get an opinion from, without looking to the crew like I was on shaky ground. She was a rock."
MacFarlane tried not to let the pressure of following up Ted, which was extremely well-received and a huge box-office hit, weigh on his mind.
Ted was the highest-grossing comedy of 2012, scooping close to US$550 million worldwide.
"I never went into this with any ideas of trying to match that level of commercial success.
It's a very different movie and I have no delusions that a comedy Western would match the success that Ted did.
"But then I didn't think Ted would do what it did ..."
As for switching from having a teddy bear as his lead to starring with Theron: "Charlize is much easier because she doesn't cost $17 million to animate.
"She comes very animated already."
A Million Ways to Die in the West opens on Thursday.
