Lucy Way Sistare Say was born 14 October 1801 in New London, Connecticut, one of ten children of Joseph and Nancy Way Sistare. While Say's early education remains unknown, it is known that she became a teaching apprentice around the year 1823 at the Pestalozzian school in Philadelphia. As the first of its kind in the U.S., this experimental school for girls was opened by Marie Duclos Fretageot (d. 1833). French naturalist/illustrator and ANSP member Charles Alexandre Lesueur (1778-1846) taught drawing three times per week in Fretageot's school, and Say received instruction from him. Say was also a temporary pupil (ca. 1824) of John James Audubon (1785-1851), although the degree of her tutelage remains unknown.

Say became acquainted with many naturalists and artists through that taught at Fretageot's school and soon became a participant in the plans laid by Robert Owen (1771-1858), William Maclure (1763-1840), and other Academy members, including naturalist Thomas Say (1787-1834) and Lesueur, to establish a utopian socialistic community on the banks of the Wabash River. On the way to New Harmony, Say became acquainted with Thomas, and on 4 January 1827, she and Thomas were married. The two remained in New Harmony while Thomas carried out scientific research and publication under wilderness conditions. While she and Thomas had no children of their own, Say taught drawing to the Owenist children at various times. Due to the frontier nature of the town, and especially from the liberal views supporting equality of the sexes advocated by community leaders Owen and Maclure, women faced fewer social restrictions in New Harmony than in eastern cities. Returning to New York City following her husband's death, Say described her new life in the east as "too circumscribed, I long for the freedom I used to enjoy when I lived on the Banks of the Wabash".

Say's drawing and painting skills were applied in earnest when she undertook to illustrate Thomas's monographic work, American Conchology. Besides furnishing drawings for 66 of the Conchology's 68 plates, Say performed much of the painstaking coloring of individual impressions, which came to number in the thousands. She was assisted in this task by two of engraver Cornelius Tiebout's children, Henry and Caroline. R.E. Banta wrote, in 1938, that these colored plates "surpass anything else produced in this country [at that time] in delicacy and accuracy of detail. Each shell is a masterpiece of miniature painting which, apparently, involved hours of labor."

The death of American Conchology's engraver in 1834 prompted Say to study the engraver's art. Following her husband's death in 1834, Say returned to New York City, where her mother and sister resided. There, she again determined to learn engraving with the purpose of completing the plates for the unfinished seventh number of the Conchology. Say's "greatest desire", expressed to entomologist Thaddeus W. Harris, was "to be able to contribute to the continuation of the Conchology by drawing and engraving". Say convinced an English engraver named Pilbrow to instruct her. She wrote that, on the basis of her attempts, "I am looked upon as being very singular, particularly since I have commenced Engraving." Say is the most probable engraver of plates 62, 65, and 67 in Conchology's final number. She also considered engraving as a possible career, but those plans were cut short when, after several months of teaching, her instructor entirely changed the nature of his business.

Say devoted her remaining years to aiding the natural sciences and maintaining her late husband's reputation. She donated his entomological collection and library to the ANSP. 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. She formed a small cabinet of her own and exchanged shell specimens with Haldeman. As part of Say's recognition by the world of science, she was elected the first female member of the Academy on 26 October 1841 and a member of its Conchological Section in 1868. She died in 1886.