Earlier this week, Miley's father Billy Ray claimed that he is "scared" for his daughter's safety.
Speaking to Access Hollywood, the comedian stated that rebellious behaviour is typical of most teenagers.
"A 16 or 18-year-old girl is going to separate from the parents no matter what," she said.
O'Donnell added: "They're going to smoke some salvia - whatever the hell that is. They're going to drink some beer. This is what happens when kids are 18 and they're trying to separate."
The star went on to say that she disagrees with Billy Ray's assertion that allowing his daughter to pursue an acting career was a mistake.
"I don't know that it necessarily had to do with [Miley] being in show business," she remarked. "I think he's doing what a lot of us are doing that have teenagers, including me, [saying], ‘What the hell is going on here? I thought I was in control of this place and now the kids are acting out. The animals are ruining the zoo'."
O'Donnell is to return to TV this autumn as the host of a daytime talkshow on the Oprah Winfrey Network.