The outbreak of the American Civil War shifted Elizabeth and Emily’s focus to the Union effort as the conflict progressed. They organized a meeting that led to the creation of the Women's Central Association for Relief, which supported the war effort by coordinating supplies and selecting women to serve as nurses. Elizabeth became chair of the registration committee and screened and trained volunteer nurses. The Blackwells faced resistance from the male-dominated medical establishment and found their roles minimized within the broader Sanitary Commission. Frustrated but undeterred, the sisters sent 100 trained nurses to the front lines before resigning from their committee roles. The sisters also built a cottage in Bloomfield, New Jersey, using funds from Madame de Noailles. The retreat provided a respite for the sisters and their patients. Elizabeth also went to Washington, D.C., as a tourist, accompanied by her friend William Elder. While there, she visited government buildings, met Dorothea Dix, and had an impromptu meeting with President Abraham Lincoln.

Elizabeth and Emily initially had no intention of founding a women's medical college, preferring to open existing institutions to women instead. However, the lackluster quality of female graduates and the proliferation of mediocre women's medical colleges in Philadelphia and Boston, which they viewed with disdain, forced them to reconsider.