She was 68.
Jacquelyn Heard, a family friend and the former mayoral spokeswoman, said the former first lady, who had been diagnosed with breast cancer more than nine years ago, died just after 6 p.m. Thursday, the Chicago Tribune reported.
She was surrounded by her husband and other family members at her home, Heard said.
"The mayor and his family would like to thank the people of Chicago for the kindness they have shown Mrs. Daley over the years and they appreciate your prayers at this time," Heard said.
Since her diagnosis, Daley had been hospitalized several times and had used a walker, crutches or wheelchair during public appearances in recent years.
But she minimized her own struggles, focusing on the needs of others, the Tribune said.
She normally stayed out of the spotlight while her husband served as mayor but had a great deal of influence on him.
As mayor, he supported causes she backed, including transforming Meigs Field airstrip into a nature park and providing public funds to an after-school charity she founded.
She and her husband had an extraordinarily close relationship in their marriage of nearly 40 years.
"They thrill at traveling, love movies and often laugh at the same things," TV and film producer Donna La Pietra told the Tribune in 2010. "These are two people who watch over each other, without being cloying or dysfunctionally protective."
In a statement, President Barack Obama called Maggie Daley "an extraordinary woman who dedicated her life to public service."
"While she will be sorely missed, her initiatives on behalf of Chicago's youth live on as national models for how to create environments for children to learn and grow outside the classroom," Obama said.
The former Margaret Ann Corbett was born July 21, 1943, the youngest and only girl among seven children, in Mount Lebanon, Pa., a Pittsburgh suburb.