O'Donnell says she does feel less angry these days, a tribute to discovering she needed to take hormones.
"I had zero levels of estrogen," she said, a discovery that was prompted by her friend Suzanne Somers, who urged her to get her levels checked.
"I started on bio-identical estrogen cream and I think it made a huge difference in my life," O'Donnell said.
While a visit to her new show reveals O'Donnell is upbeat, even zany in her opening monologue, she is also reflective and personal in an interview with Carrie Fisher about her weight loss and depression. Two topics close to O'Donnell's heart.
"That was a challenge my whole life," she said. "I was so grateful that I had gotten on medication after Columbine. I don't know how I would have gotten through 9/11...They say it's PTSD, I don't know, but it's a very big issue. In fact, when I took this job, I did say to Oprah, 'I'm pretty stable.' I'm doing really well, but I have to tell you, a world catastrophe, probably gonna need a week off."
With therapy and medication, the comedian says she is now feeling the best she has felt in a long time. And for O'Donnell, there is more to life than worrying about being a celebrity. Raising her four kids, Parker, 16, Chelsea, 14, Blake, 12, who were adopted, and Vivienne Rose, 9, who was conceived through artificial insemination, has been the most important thing to her.
"It is the best thing I ever did," O'Donnell said. "People sometimes say to me, 'oh, it was great of you to adopt,' and I say no it was greedy...I want to look into the eyes of that woman and that man who created those children and say, 'thank you, because you made my life worth living.'"
O'Donnell first married Kelli Carpenter, a former Nickelodeon marketing executive, in 2004. The couple divorced three years ago, and O'Donnell said she tried to date, but it wasn't easy.
By happenstance, she met her current girlfriend Michelle Rounds while standing in line at a Starbucks.
"I thought she was a 28-year-old heterosexual girl because that's what she looked like to me, and she's a 40-year-old gay woman," O'Donnell said. "My gaydar was way off."
One thing is for sure about the talk show host, she is not afraid of making a strong comeback. For O'Donnell, success means finding "a beautiful mix" of balance and happiness.