"After much prayer and months of careful thought, I have decided that next season - season 25 - will be the last season of 'The Oprah Winfrey Show,'" Oprah announced.
Winfrey told the audience that she loved "The Oprah Winfrey Show," that it had been her life and that she knew when it was time to say goodbye. "Twenty-five years feels right in my bones and feels right in my spirit," she said.
She was teary-eyed as she thanked her viewers who had invited her into their homes and lives over the past two decades.
News of the last season has many longtime viewers wishing Oprah would stay on the air on ABC7.
"It's sad, it's sad because everyone looks up to her and they believe what she says, and she has great guests on her show," said Oprah fan Debbi Gardner-Codron.
"I mean, we're talking about, arguably, the most powerful woman in America, certainly the most powerful black woman in America. So it goes without saying that she has had some sort of impact, whether directly or indirectly, on I think everyone," said fan Walter Clark.
Winfrey talked about being nervous when the program debuted on Sept. 8, 1986.
"I certainly never could have imagined the yellow brick road of blessings that have led me to this moment," the 55-year-old day-time host said.
Winfrey is expected to start up a new talk show on the Oprah Winfrey Network. OWN is to replace the Discovery Health Channel and is projected to debut in January 2011 in some 80 million homes.
"[It's] not surprising, of all the things she's said lately and having her own network coming up," said Oprah fan Marly Peet.
Winfrey offered no specifics about her plans for the future, except to say that she intended to produce the best possible shows during her last 18 months on the air.
"Over this holiday break, my team and I will be brainstorming new ways that we can entertain you and inform you and uplift you when we return here in January," she said. "And then, season 25 - we are going to knock your socks off."
"The Oprah Winfrey Show" has been a top-rated talk show for more than two decades, airing in 145 countries worldwide and watched by an estimated 42 million viewers a week in the U.S. alone.
From her support of President Obama to interviewing big names from around the world, and tackling tough issues, fans say they'll miss the conversations Oprah facilitated in households across America.
"Her show really was the pinpoint of a lot of issues and you always wanted to hear what she had to say, what Oprah had to say, before you had a comment yourself," said Oprah fan Julius Robinson.
Winfrey's 24th season opened this year with a bang, as she drew more than 20,000 fans to Chicago's Magnificent Mile for a block party with the Black Eyed Peas. She followed with a series of blockbuster interviews - Mike Tyson and Evander Holyfield, Whitney Houston and ESPN's Erin Andrews, and just this week, former Alaska governor and GOP vice presidential candidate Sarah Palin.
Winfrey started her broadcasting career in Nashville, Tenn., and Baltimore, Md., before relocating to Chicago in 1984 to host WLS-TV's morning talk show "A.M. Chicago" - which became "The Oprah Winfrey Show" one year later. She set up Harpo the following year and her talk show went into syndication.
You can watch Oprah make the announcement, and her reasons behind it, right here on ABC7 at 3 p.m. PT.
The Associated Press contributed to this report.