The Winthrop Woman is Anya Seton's story of Elizabeth, or "Bess" Fones, who is a niece of the venerable John Winthrop. Winthrop became the first governor of the New Plymouth colony in America., and dominated his people with harsh puritanical religion and punishment. His task was huge and daunting, and he became quite cruel and radical. His relationship with his niece, Bess, was tenuous. He whipped Bess in front of the entire family for a childish act of deception and later resented her marrying his son, her first cousin. Bess was too much a free spirit for John's liking, and it fell to him to arrange her marriages and protect her, being her uncle and also father, by marriage.

Elizabeth longs for freedom and autonomy. She feels traumatized forever over the whipping she received at the hand of John Winthrop as a child, and experiences the constraints of the intensive male oppression of the times in which she lived. Her religious faith is thin and, unlike her beloved mother-in-law, Margaret, she is unable to turn to the Bible to find comfort and submission. Bess maintains an open heart and mind toward those who are different, unlike the Puritan family of which she is a part.

An ironic aspect of Bess's drama is that, although she married Henry (Harry) Winthrop, her first cousin, she was always in love with his brother, Jack. When Harry died, Jack had already become engaged to Bess's sister, Martha, and a marriage between them was never even a possibility. Bess settles for an arranged marriage to Robert Feake, whose mental illness finally debilitates him entirely. Bess manages to buy a large piece of property, a feat unheard of for women of her time. Bess endures an inordinate amount of strife, turmoil, and danger as a colonist in the New World. The competition among countries for American land, the shifting borderlines among the colonies, and the influences of zeal, power, fear, and humility color her life. Further complicating her story are her arranged marriage to a mentally imbalanced man and the threats of being separated from the man she loves. Considered a black sheep for her progressive religious thinking, Bess is tested and tormented until she finally finds a sense of spiritual peace.