"Meghan and Harry do not need my help figuring out what's best for them," Winfrey told the outlet. "I care about them both and support whatever decisions they make for their family."
Meghan and Harry's royal departure, dubbed "Megxit" by British tabloids blindsided by the news, took their own family members by surprise this week as Buckingham Palace rushed to release a statement downplaying the couple's hasty split.
"Discussions with The Duke and Duchess of Sussex are at an early stage," a Palace spokesman told Fox News late Wednesday. "We understand their desire to take a different approach, but these are complicated issues that will take time to work through."
The spokesman added that "nothing is being ruled out."
Winfrey was one of the world's biggest stars to attend the Duke and Duchess of Sussex's nuptials in May 2018.
While dozens of A-listers have backed the royal couple's monumental decision, Page Six reported Thursday that Winfrey was "one of the first people" Meghan and Harry consulted, in addition to getting advice from the Obamas and George and Amal Clooney.
In a statement to Us Weekly this week, Markle's estranged father, Thomas Markle, shared he was "disappointed" to learn of the split.
Meanwhile, Markle's estranged sister Samantha Markle called Archie's parents' choice a "slap in the face."
Fox News' Jessica Napoli contributed to this report.