The talk show host, who endorsed Hillary Clinton’s campaign, hinted at throwing her hat into the ring.
Winfrey said Mr Trump’s election had made her re-evaluate her previous scepticism about running for President.
"I never considered the question even a possibility," she told David Rubenstein on his Bloomberg Television programme when pressed about whether she might consider running.
"I just thought, 'Oh… oh?'"
Referring to Mr Trump, Mr Rubenstein said: "It's clear you don't need government experience to be elected president of the United States".
"That's what I thought," she continued. "I thought, 'Oh, gee, I don't have the experience, I don't know enough.' And now I'm thinking, 'Oh.'"
Unfortunately, for the legion of fans who would love to see her in the White House, she later added: "No, that won't be happening. But - I mean I did used to think that you had to know so much more than I thought you have to know."
Back in January, Winfrey made it clear she would never run for President.
“Is there any other charismatic African-American woman that both sides of the political aisle really love?” Stephen Colbert asked after a reference to former first lady Michelle Obama, sparking a round of applause from the show's audience.
But Winfrey insisted: “Never. No, no, it’s not my thing.”
Winfrey was a supporter of Ms Clinton and insisted she had no plans of joining the billionaire property developer as his running mate back in June, saying “Donald, I’m with her!” and arguing her candidacy was a pivotal moment for women.
But Winfrey did face backlash for her seemingly positive remarks about Mr Trump in the wake of his victory. At the time, she suggested the President-elect has been “humbled” by his shock victory and “hope” lived on. She later addressed the criticism levied at her, saying she had been wrong to talk about everyone taking a "breath".
“I couldn’t breathe after the election,” Winfrey said. “My mistake, and this is what I know to be true, is that you can never talk about everybody. Don’t talk about ‘What you should do.’ You can only speak for yourself. What I should have said was, ‘I just took a breath.’ What I said was, ‘Everybody take a breath - #HopeLives.’"
Winfrey’s capacity to significantly influence public opinion has been dubbed “The Oprah Effect”. The media mogul, who is the first and only multi-billionaire black person in the US, is a significant influencer in the country and one estimate predicted that her endorsement of Mr Obama between 2006 and 2008 delivered over a million votes in the 2008 Democratic primary race
The unexpected victory of President Trump, a former reality TV star, is an example of how the line between celebrity and politics has become increasingly blurred in America. There has also been speculation around whether Facebook CEO's Mark Zuckerberg and rapper Kanye West could one day run to be President.
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