Dr. Will Halstead (Nick Gehlfuss) has to balance the stress as the ER's supervising Attending Physician with his relationship with Dr. Natalie Manning (Torrey DeVitto), emergency pediatrics resident. Rising star heart surgeon Dr. Connor Rhodes (Colin Donnell) tackles a new and exciting challenge in the hospital that keeps him in close proximity to his former rival and highly competitive Cardiothoracic Fellow, Dr. Ava Bekker (Norma Kuhling). Dr. Daniel Charles (Oliver Platt) remains the Sherlock Holmes of psychiatry. Former Navy flight surgeon Dr. Ethan Choi (Brian Tee) brings his battlefield skills to the front lines of Chicago's busiest ER, the go-to place for victim's of the city's gun violence. Sharon Goodwin (S. Epatha Merkerson), the venerable head of the city's largest hospital, is under intense fiscal scrutiny to preserve the bottom line while continuing to ensure that all patients receive nothing short of quality care and compassion. To further complicate matters, she now finds herself having to answer to the newly hired C.O.O., Gwen Garrett (guest star Heather Headley).

April Sexton (Yaya DaCosta) is a smart, bold and intuitive ER nurse who is newly single, having broken off her romantic relationship with Ethan. Maggie Lockwood (Marlyne Barrett) is the confident charge nurse and the eyes, ears and brain of the emergency department. Lending his skills in the ER is April's ambitious brother, Dr. Noah Sexton (guest star Roland Buck III).