Speare was born in Melrose, Massachusetts to Harry Allan and Demetria Simmons George. Her childhood, as she later recalled, was "exceptionally happy" and Melrose was "an ideal place in which to have grown up, close to fields and woods where we hiked and picnicked, and near to Boston where we frequently had family treats of theaters and concerts." She had an extended family with one brother and many aunts, uncles, and cousins, and most importantly, very loving and supportive parents. Speare lived much of her life in New England, the setting for many of her books.

Speare discovered her gift for writing at the age of eight and began composing stories while still in high school. After completing her Bachelor of Arts degree at Smith College in 1930, she earned her Master's degree in English from Boston University and taught English at several private Massachusetts high schools from 1932 to 1936. In 1936 she met her future husband, Alden Speare, and together the two moved to Connecticut where they married and raised two children; Alden, Jr., who was born in 1939, and Mary in 1942. Although Speare always intended to write, the challenges and responsibilities of being a mother and wife drained her of any free time. Speare began to focus seriously on literature when her children were in junior high school.

Speare's first published work was a magazine article about skiing with her children. She also wrote many other magazine articles based on her experiences as a mother, and even experimented with one-act plays. Eventually her work saw circulation in Better Homes and Gardens, Woman's Day, Parents, and American Heritage.

Speare published Calico Captive, her first novel, in 1957. The next year she completed her second historical fiction work, The Witch of Blackbird Pond, which won numerous awards, including the Newbery Medal. Ideas and inspiration for both books came to Speare while she was researching the history of New England and Connecticut, respectively. She earned her second Newbery Medal for her third book, The Bronze Bow, published in 1961. In 1984 The Sign of the Beaver was published and received a Newbery Honor Citation, the Scott O'Dell Award for Historical Fiction, and the Christopher Award. In 1989, Speare received the Laura Ingalls Wilder Award for her distinguished and enduring contribution to children's literature.

Speare died of an aortic aneurysm on November 15, 1994 in Northwest General Hospital in Tucson, Arizona.