On July 25, 2016, Warren delivered the keynote address on the opening night of the Democratic National Convention in Philadelphia. She became the third woman, following Representative Barbara Jordan and Governor Ann Richards, to receive this honor. During her speech, Warren drew strong contrasts between Democratic candidate Hillary Clinton and her Republican opponent, Donald Trump.

During this time, Warren also addressed controversy surrounding her claims of Native American heritage. She released a statement explaining, "Growing up, my mother and grandparents often talked about our family's Native American heritage. As a kid, I never thought to ask them for documentation—what kid would?" She further stated that she never used her reported heritage for personal gain in school or professional settings.

Senate Election Campaign

On September 14, 2011, Warren announced her candidacy for the U.S. Senate seat in Massachusetts, challenging Republican incumbent Scott Brown. Around the same time, a speech she gave at a small meet-and-greet went viral on YouTube. In the video, she explained how societal infrastructure and public services are funded by taxes and benefit all Americans. Her remarks resonated with populist audiences and helped boost her visibility in the campaign.

Despite a strong start, Warren's campaign faced scrutiny in 2012 over her claimed Native American ancestry. Investigations by outlets such as the Boston Herald and statements from Cherokee genealogists questioned her familial assertions. Nonetheless, Warren continued to stand by her family's oral history.

Democratic Nomination and Victory

In June 2012, Warren secured the Democratic nomination for the Senate race. Her contest with Senator Scott Brown remained close, with a September 2012 Public Policy Polling survey showing Brown holding a five-point lead. However, Warren gained momentum later that month after speaking at the Democratic National Convention in Charlotte, North Carolina. Her speech received favorable reviews and helped her gain a narrow lead in the polls, contributing to her eventual election victory in November 2012.