The 40-year-old Family Guy creator stars as Albert Stark in the new movie, a timid sheep farmer who falls in love with a woman (Charlize Theron as Anna) with a dangerous outlaw ex-husband (Liam Neeson as Clinch). Amanda Seyfried, Giovanni Ribisi, Neil Patrick Harris and Sarah Silverman also appear as Albert's first love Louise, cobbler Edward, mustache expert Foy and prostitute Ruth.
MacFarlane wrote, produced and directed the film, and tells the morning program his assembled cast was nearly perfect.
"We did not get Steve Buscemi for Neil's part," he jokes in the interview. "So we had to settle for Neil."
"I went out to Paul Rudd [to play Albert] and he said no," he continues of his own role. "I'm like the poor man's Paul Rudd."
The actor and director goes on to admit "a comedy western is not the most economically [successful idea]," and jokes that he likes to "set [himself] up for failure." His first feature film, Ted, earned almost $550 million at the box office, and MacFarlane hopes to replicate his success with A Million Ways to Die in the West.
"They've promoted the raunch factor, which is there," he says of the new movie. "It is, believe it or not -- you go to see the movie from start to finish -- it is a romantic comedy of sorts. As shocking as that may sound. It is an old-fashioned western in that regard."
A Million Ways to Die in the West debuts in theaters May 30.