[4] The Lilly Endowment has historically focused on three primary grant areas: community development, education, and Christianity.

[10][7][needs update] The private family foundation is a separate entity from the Eli Lilly and Company pharmaceutical firm, and maintains its headquarters in a different location.

The nonprofit foundation has its own board of directors to manage its affairs and an executive committee (trustees) that reviews grant requests.

[11] Although it has provided gifts with a national and global reach, the Lilly Endowment's primary geographic focus has been in Indianapolis and in Indiana.

[12] Other major gifts helped to fund construction projects in downtown Indianapolis, including the Indiana Convention Center, the Hoosier Dome (the city's first, domed stadium), and restoration of several of the city's historic buildings, including the Hilbert Circle Theater, the Indiana Theater, and grants to construct the Indianapolis Zoo, Eiteljorg Museum of American Indians and Western Art, and sports facilities on the Indiana University – Purdue University Indianapolis campus and elsewhere in the city.

Lilly supported a wide variety of religious endeavors, which he considered an important means of promoting character development.