Witherspoon and actress Mindy Kaling both appeared on Winfrey's Super Soul Sunday for an interview which will appear in the next issue of O magazine.
The three women are costars in the new fantasy film A Wrinkle in Time, but their discussion took a very real turn when Winfrey asked her guests, "What's the most difficult decision you've had to make to fulfill your destiny?"
Witherspoon revealed she had been in an abusive relationship - without naming her abuser - and said that choosing to leave that relationship changed her life forever.
The Legally Blonde star explained that she had been the victim of verbal and psychological abuse, and choosing to leave the relationship made her a stronger person.
"I could never be the person I am today. ... It changed who I was on a cellular level, the fact that I stood up for myself," she told the host, adding that since leaving the relationship she's changed completely.
"People say to me that knew me then, 'You're a completely different person.' I didn't have self-esteem. I'm a different person now and it's part of the reason I can stand up and say, 'Yes, I'm ambitious' — because someone tried to take that from me before."
Witherspoon explained what finally pushed her to end the relationship, and after her dramatic confession the host shared her own experience with an abusive partner.
Last year, Witherspoon also revealed she had been sexually assaulted by a film director when she was just 16 years old.
The actress says her experience with abuse influenced her decision to produce and star in HBO's Big Little Lies, which features a story-line about domestic abuse.
"There wasn't a woman there that hadn't been affected by abuse," the actress said about the cast and crew on the series.
Witherspoon told Winfrey that her decision to leave the abusive relationship came when "A line got drawn in the sand and it got crossed, and my brain just switched."
"I just couldn't go any further," she explained. "It was profound and I was young, really young."
In response, the TV host shared her own story about realizing she was in an abusive relationship.
"I lived in that superior, better-than-thou space where, 'As long as he doesn't hit me, he can say anything, he can do anything, but as long as he doesn't hit me,'" Winfrey said.
But after her hand was slammed into a door, Winfrey says she realized she "had become that woman who would allow myself to be psychologically, verbally assaulted," and walked away.
If you or someone you know is affected by domestic abuse, you can call the National Domestic Violence Hotline at 1-800-799-7233 or visit their website.