Melissa Gilbert is hoping to represent Michigan's 8th District as a Democrat in the House of Representatives.
"I'm running for Congress to make life a little easier for all the families who feel they have fallen through the cracks in today's economy," she said.
The 51-year-old played Laura Ingalls Wilder on the television show, which was popular in the '70s and '80s.
Making the announcement with a statement on her 2016 campaign website, she added: "I believe building a new economy is a team effort, and we need to bring fresh voices to the table to get the job done."
The programme in which she made her name was based on the children's book series written by Laura Ingalls Wilder, a pioneer recounting her settler childhood in Wisconsin and Kansas.
Her portrayal of the young Laura made Ms Gilbert a child star, with Michael Landon starring as her father Charles.
Ms Gilbert has served two terms as president of the Screen Actors Guild, a job held by Ronald Reagan before he also chose a political path that eventually took him to the White House.
After Little House on the Prairie, which came to an end in 1983, she went on to act in dozens of television series and TV movies.
An actress famed for starring in Little House on the Prairie as a child has announced she is running for Congress.