Catherine Greene, the widow of General Nathanael Greene, played a significant role in Whitney's early career. She provided him with lodging and support at Mulberry Grove Plantation, where he invented the cotton gin. Their relationship was one of patronage and mentorship.

At the age of 52, Whitney married Henrietta Edwards, the daughter of Pierpont Edwards, a prominent politician and judge. This marriage brought him into a well-connected and influential family.

Eli and Henrietta Whitney had four children: Eli Whitney III, Susan Edwards Whitney, Frances Edwards Whitney, and Elizabeth Fay Whitney. His family life provided him with a sense of stability and personal fulfillment in his later years.