Mondale, 83, who had just entered hospice during the weekend, was surrounded by her husband, sons and family members when she passed, the (Minneapolis) Star Tribune reported.
"We are grateful for the expressions of love and support we have received. Joan was greatly loved by many. We will miss her dearly," Walter Mondale said in a statement.
She also is survived by her sons Ted and William. A daughter, Eleanor, died of brain cancer in 2011.
During her tenure as the vice president's wife, Mondale became known as "Joan of Art," a promoter of the arts, particularly American folk art. It was a niche she carved out for herself on the political and cultural landscape.
She wrote a book titled "Politics and Art" and worked in a pottery studio she shared with three others.
She served on numerous art committees and museum boards, including a job as honorary chairwoman of the Council on the Arts and Humanities during the Carter administration.
During her husband's 1984 presidential campaign, she discussed how she saw her role.
"Nine out of 10 women will work at some time in their lives," she said. "I am the unusual one, because I am a full-time volunteer. I am a vanishing breed.
"I have my own identity, separate and independent of my husband's. People know who I am."
Mondale noted at that time she admired former first lady Eleanor Roosevelt as "a woman in her own right."
"I have always admired activist first ladies," she said, recalling she met Roosevelt in her later years. "She really broke ground. She stood out as a woman in her own right with her husband's approval."
A veteran campaigner, Mondale toiled in the political vineyard from 1960, when her lawyer husband sought the job of attorney general of Minnesota. Through two Senate seats and the 1976 and 1980 national campaigns, she went to voters he could not reach because of time or distance.
"I'm his surrogate. I'm his advocate. I enjoy campaigning," she said. The crinkling at the corners of her eyes suggested she meant it.
Joan Adams was born Aug. 8, 1930, in Eugene, Ore. She spent some of her childhood in Ohio and went to high school near Philadelphia as the family was following her father, a Presbyterian minister, from job to job as a college chaplain.
Her father's next stop was MacAlester College in St. Paul, Minn., where she earned her undergraduate degree in history. Three years later, she met the son of a Methodist preacher on a blind date. A 53-day engagement led to a candlelight wedding service, conducted by her father, Dec. 27, 1955.