This is occurs mostly in the Ohio Rv. watershed and lower Great Lakes region. It is largely restricted to base-rich soils in relatively undisturbed, mesic to subxeric woods. Along with several other white-flowered herbs (especially Sanguinaria) it is one of the first species to bloom in spring, mostly in early April but ranging from early Mar to mid-Apr; Short (1828) noted "flowers appear about the 30th of March". Jeffersonia has had much medicinal use, and appears to have chemistry similar to Podophyllum. However, there has been little definitive research on such applications in diphylla (Ram 2010, Jeong & Sivanesan 2016).