O'Donnell, the third of five children, was born and raised in Commack, Long Island, New York. She is the daughter of homemaker Roseann Teresa (nee Murtha) and Edward Joseph O'Donnell, an electrical engineer who worked in the defense industry. O'Donnell's father had immigrated from County Donegal, Ireland, during his childhood, and her mother was Irish American; O'Donnell was raised Roman Catholic. Her older brother is Daniel J. O'Donnell, now a member of the New York State Assembly.

In 2011, O'Donnell began producing material for the Oprah Winfrey Network (OWN). In May 2011, The Doc Club with Rosie O'Donnell premiered, a show where O'Donnell moderates live panel discussions following premieres of OWN Documentaries. She has hosted specials for Becoming Chaz in May 2011 and Miss Representation in October 2011.  In fall 2011, O'Donnell began full-time work on her new show, The Rosie Show, for OWN. The show taped at the Chicago studio formerly home to The Oprah Winfrey Show. The show debuted on October 10, 2011, to generally positive reviews.  OWN canceled The Rosie Show on March 16, 2012, with the last show taped March 20, on the eve of O'Donnell's 50th birthday. The final show aired on OWN on March 29, 2012. In a statement, Oprah Winfrey said "I thank Rosie from the bottom of my heart for joining me on this journey. She has been an incredible partner, working to deliver the best possible show every single day. As I have learned in the last 15 months, a new network launch is always a challenge and ratings grow over time as you continue to gather an audience. I'm grateful to Rosie and the dedicated Rosie Show team for giving it their all." O'Donnell responded to the cancellation by thanking her viewers and the host city of Chicago: "I loved working with Oprah in the amazing city of Chicago. I was welcomed with open arms and will never forget the kindness of all I encountered. It was a great year for me--I wish the show was able to attract more viewers--but it did not. So I am headed back to my home in New York--with gratitude. On we go!"

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