Edwards died of cancer at her home in Chapel Hill, North Carolina, surrounded by her family, the family said in a statement.
"Today we have lost the comfort of Elizabeth's presence but she remains the heart of this family. We love her and will never know anyone more inspiring or full of life," the statement said.
Edwards was first diagnosed with breast cancer and treated in 2004. In 2007, the cancer returned and spread.
She wrote two best-selling books, "Resilience" and "Saving Graces," about her battle with cancer and the scandal surrounding her husband, a wealthy trial lawyer who served as a U.S. senator from North Carolina and twice ran for president.
Her husband was a rising star in the U.S. Democratic Party who was selected as Massachusetts Senator John Kerry's running mate when Kerry lost narrowly to Republican incumbent George W. Bush in 2004.
"Elizabeth Edwards was an incredibly loving, giving, and devoted mother," Kerry said in a statement.
President Barack Obama in a statement called her "a tenacious advocate for fixing our health care system and fighting poverty," and said the county "has benefited from the voice she gave to the cause of building a society that lifts up all those left behind."
John Edwards' personal and political fortunes changed after the National Enquirer, a tabloid newspaper, began reporting on his affair with a campaign aide named Rielle Hunter as he sought the 2008 Democratic presidential nomination. John Edwards initially dismissed the reports as "tabloid trash."
Elizabeth Edwards and her husband announced in January 2010 that they had separated after 32 years of marriage. The split came less than a week after John Edwards admitted that he had fathered a baby with Hunter. The girl was 2 years old when he acknowledged he was her father.
Elizabeth Edwards' marriage disintegrated even as she battled terminal cancer. On December 6, 2010, she said in a Facebook posting: "I have been sustained throughout my life by three saving graces, my family, my friends, and a faith in the power of resilience and hope."
"These graces have carried me through difficult times and they have brought more joy to the good times than I ever could have imagined. The days of our lives, for all of us, are numbered. We know that," she added.
Elizabeth and John Edwards endured a family tragedy before he entered politics.
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