Born in Memphis, Tennessee, she soon experienced her parents' divorce, from which her father, Millsaps Fitzhugh, gained custody, and so she lived with him in the South. She attended Miss Hutchinsons' School and three different universities, without obtaining a degree.Her first book was Suzuki Beane in 1961, which was a children's picture book that was intended as a parody of Eloise. She illustrated it, working closely with author Sandra Scoppettone.
Her most well-known book was Harriet the Spy, which was published in 1964 to a great deal of controversy. Two minor characters in the book, Beth Ellen and Sport, were featured in two of Fitzhugh's later books, The Long Secret and Sport.
Fitzhugh illustrated many of her books and had works exhibited in Banfer Gallery, New York, in 1963, among many other galleries.
