The Family Guy creator received a green light from Fox to reboot the 1960s cartoon series about Stone Age man Fred Flintstone, his family and his friends.
MacFarlane was on hand to address the news when the announcement was made earlier today at the network's upfront presentation in New York.
He said: "The very first cartoon character I drew at age 2 was Fred Flintstone. So it's appropriate that events have come full circle, allowing me to produce the newest incarnation of this great franchise.
"Plus, I think America is finally ready for an animated sitcom about a fat, stupid guy with a wife who's too good for him."
The actor went on to promise that the show will appeal to old fans, though it will be updated for the modern-day audience.
"The characters will look the same but the only thing that will change is the stories," MacFarlane said. "What's the [prehistoric] version of an iPod?"
Kevin Reilly, President of Entertainment for Fox Broadcasting Company, added: "The Flintstones are among the funniest and most beloved characters in television history, and we can't wait to introduce them to a whole new generation on Fox.
"Fox has long been home to iconic families like the Simpsons and the Griffins, so I have no doubt that the Flintstones and the Rubbles are going to fit right in on our air."
Actress Edie Falco previously mentioned that a Flintstones remake was on the way, stating that it could be a vehicle for her reunion with actor James Gandolfini, with whom she starred on The Sopranos.
MacFarlane already has three animated comedies on the Fox network - Family Guy, American Dad! and The Cleveland Show. All three series were recently renewed for new seasons.
The 37-year-old comedian is currently developing a movie as well. Titled Ted, the film tells the story of boy that made a Christmas wish that his teddy bear would come to life only to find the bear still by his side once the boy is grown.
The Flintstones will go into production this year for a scheduled premiere in 2013.