While an elementary student, she started her career in broadcasting by giving videotaped English lessons for the Korean Educational Development Institute.

[4] The family moved back to San Antonio, where she attended Douglas MacArthur High School, from which she graduated in 1991.

On May 6, 2019, Susan Zirinsky, president of CBS News, announced that O'Donnell had been named anchor and managing editor of the CBS Evening News beginning on July 15, 2019,[10] and also would be the lead anchor of political events for the network and continue as a contributing correspondent for 60 Minutes.

[14] The interview made headlines for the Pope's discussion of surrogacy, gay marriage and Female Priests.

O'Donnell said that her daughter's first name had been suggested by Tim Russert, who died three weeks prior to Riley's birth.

[24] In fall 2016, O'Donnell was diagnosed with melanoma 'in situ', meaning the cancer was contained to the epidermis and had not yet spread to the dermis and metastasized.

O'Donnell won the Sigma Delta Chi Award for Breaking News Coverage for the Dateline NBC story "DC In Crisis," which aired on the night of September 11, 2001.

That same year, this story was given an honorable mention from the White House Correspondents' Association for the Edgar Allan Poe Award.