Because of the college's strict codes of gender segregation at the time, Mitchell had to circumvent the all-male Harvard Yard in order to reach Harvard University's Museum of Comparative Zoology, where she worked in the Radcliffe Zoological Laboratory.

[9] In 1916, influenced by the work of John Dewey, Mitchell cofounded the Bureau of Educational Experiments (BEE) in New York City to study and develop optimal learning environments for children.

[12] Mitchell wrote over twenty books,[7] including North America (1931),[13] Streets: Stories for Children Under Seven (1933), Horses Now and Long Ago (1938), The Here and Now Story Book (1938),[14] See What's in the Grass (1945),[15] Our Children and Our Schools (1950),[16] and Believe and Make Believe (1956).

[17] She also wrote a memoir of her marriage, Two Lives: The Story of Wesley Clair Mitchell and Myself (1953).

[20] Lucy Sprague Mitchell died in 1967, aged 89 years, in Palo Alto, California.