Dr. Shaun Murphy and Dr. Alex Park treat two patients who collapse at the local airport and whose symptoms point to an infection that may become airborne. The staff races to contain the infection before it spreads to the rest of the patients in the ER, resulting in a hospital quarantine during the holidays.

The hospital is still in quarantine as Dr. Shaun Murphy continues to be overwhelmed by the chaos and noise in the emergency room; Dr. Morgan Reznick struggles to keep her patients alive, and Dr. Audrey Lim fights for her life. Meanwhile, Dr. Neil Melendez and Dr. Claire Browne must find a way to complete their patient’s bone marrow transplant, despite the quarantine.