Drabble has acknowledged the source of the title to be in Christ's words: "But whoso shall offend one of these little ones who believe in me, it were better that a millstone were hanged about his neck and that he were drowned in the depth of the sea" (Matthew 18:6).

The parallel between Christ's words and the plot of the novel is established through the innocent though illegitimate baby, Octavia, the "little one", who is subject to harm, her congenital heart defect rendering her vulnerable in the extreme.

Set in not-quite-yet Swinging London, The Millstone focuses on the life of Rosamund Stacey, an attractive Cambridge graduate who is writing her thesis on early English poetry while living alone in the spacious flat of her parents, who have gone to Africa for a year on a philanthropic mission.

Too shy to tell him that she has fallen in love with him, and now believing that he is bisexual, she lets George vanish from her life as quickly as he entered it, in the ensuing months only occasionally listening to his voice on the radio.

However, in a letter to her sister Beatrice expresses her shock and disbelief and urges Rosamund either to have an abortion or to give birth to the baby and put it up for adoption immediately afterwards, and then carry on with her life and academic career as if nothing had happened.

She finds a true friend in Lydia Reynolds, a young novelist who happily takes her up on her offer to share her flat with her in return for the occasional babysitting job once her child has been born.

Rosamund's parents are informed about the existence of their grandchild through a letter from Octavia's surgeon, who happens to be an old acquaintance of theirs, but they tactfully decide not to disturb their daughter's new life and stay abroad for another year rather than return for Christmas as planned.