The hospital is the flagship medical center for Eskenazi Health, founded in 1859 as Indiana's oldest public healthcare system.

[1] Many of Eskenazi Hospital's 4,620 medical staff[2] are provided by a mix of faculty, residents, and students of the adjacent Indiana University School of Medicine.

On November 3, 2009, 85 percent of Marion County voters approved a major bond referendum for the development of a new public medical center.

[6] Construction for the $754 million Sidney & Lois Eskenazi Hospital started in 2010 and opened to the public on December 7, 2013.

[8] Eskenazi Hospital's front entrance is flanked by a 1.5 acres (0.61 ha) plaza, called The Commonground, which features 5,000 perennial plants, a trellis sculpture, lawns, public seating, Healing Waters dry-deck fountain, the St. Margaret's Hospital Guild Limestone Falls, and the Frank & Katrina Basile Pavilion.

In 2016, the Physicians Committee for Responsible Medicine ranked Eskenazi sixth of 24 hospitals recognized nationwide for providing fresh vegetables, whole grains, cholesterol-free entrees, and soy milk.

[2] The Eskenazi Health Art Collection is part of the hospital's commitment to wellness and includes more than 30 artworks on public display.