The Rosie Show premiered in October 2011 on Oprah Winfrey's cable network but has consistently suffered from low ratings.
Winfrey has now announced that the programme will film its final episode on March 20, with an air date set for March 30.
"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," Winfrey said in a statement.
"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 released her own statement following the announcement, thanking Winfrey for the opportunity to host The Rosie Show and insisting that there are no hard feelings about OWN's decision not to continue with the show.
"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," O'Donnell explained.
"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!"
Earlier this month, it was suggested that O'Donnell was considering moving The Rosie Show to New York City in an effort to secure more high-profile guests.