On Monday Edwards said she had stopped treatment for cancer after doctors informed her that any further therapy would be useless.
President Barack Obama offered his condolences on Edwards' passing, hailing her as a "tenacious advocate for fixing our health care system and fighting poverty."
"Through all that she endured, Elizabeth revealed a kind of fortitude and grace that will long remain a source of inspiration," he said in a statement.
Secretary of State Hillary Clinton also said she was 'deeply saddened" by Edwards' death.
"America has lost a passionate advocate for building a more humane and just society, for reforming our health care system, and for finding a cure for cancer once and for all," she said.
Edwards had first noticed a lump on her breast during the 2004 campaign but kept the news a secret until it ended with George W. Bush defeating her husband and Democratic presidential candidate John Kerry.
She received surgery and treatment for the disease over the next few months and the cancer went into remission before surfacing again in 2007, when her husband was mounting another campaign for the White House.
The two insisted they would press ahead in spite of the disease, and Edwards went on to serve as a top political advisor and spokesperson for her husband, particularly on the hot-button issue of health care reform.
Americans only learned later that her husband had cheated on her with a campaign filmmaker while he was preparing his second White House run and that she had found out about the affair while being treated for cancer.
John Edwards, a North Carolina senator before he joined the presidential ticket in 2004, went public with the long-rumored affair in August 2008, and in January of this year admitted to fathering a child with the filmmaker.
Edwards said her husband had told her of the affair in 2006 and that she viewed it as a painful but private issue.
She went on to write about her struggle with cancer and her husband's infidelity in the bestselling 2009 memoir "Resilience: Reflections on the Burdens and Gifts of Facing Life’s Adversities."
The couple were no strangers to tragedy. In 1996, their 16-year old son Wade was killed in a car accident.
US media outlets said that Edwards' family had gathered around her in her final hours, including her husband, who had moved back to help care for her.
She is survived by three children, two under the age of 13.
"The days of our lives, for all of us, are numbered," Edwards said in what became a parting message on her Facebook page Monday.
"We know that. And, yes, there are certainly times when we aren't able to muster as much strength and patience as we would like. It's called being human."
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