She joined a group of prominent scientists, educators, and artists on a keelboat known as "Boatload of Knowledge," which traveled along the Ohio River from Pittsburgh, Pennsylvania during the winter of 1825–1826 to form a utopian socialist community in New Harmony, Indiana.

Due to the frontier nature of the town, and especially from the liberal views supporting equality of the sexes advocated by community leaders Robert Owen and William Maclure, women faced fewer social restrictions in New Harmony than in other eastern American cities.

When Say returned to New York City in 1834 following her husband's death, she described her new life as "too circumscribed, I long for the freedom I used to enjoy when I lived on the Banks of the Wabash.

"[2] Say's drawing and painting skills were applied in earnest when she undertook to illustrate Thomas's monographic work, American Conchology.

In 1840, Say began a correspondence with Samuel Stehman Haldeman (1812-1880), whom she viewed as a capable successor to her husband's research in conchology and entomology.