Rhimes told TV Guide that there are some tough times ahead for the duo, played by Sandra Oh and Kevin McKidd.
"I think it's going to affect every corner of their lives," she said.
"Some of the performances that Sandra and Kevin are turning in are, like, people are crying while watching the dailies. It's unbelievably good what they're doing."
Rhimes acknowledged that fans are "dedicated" to the couple, adding: "I'm not going to say whether or not they're going to break up or not because, honestly, that's kind of not the point in this.
"But I feel like they're two people who really want to be together, who are fighting to make it work. What that's going to mean is it's going to be fairly painful, even if they make it work. It's going to be a painful journey."
Rhimes has previously suggested that everything "blows up to holy hell" for Cristina and Owen in upcoming episodes.
The show airs on Thursdays at 9/8c on ABC.
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