Dr. Rhodes begins a fellowship in cardiothoracic surgery, only to have problems with his new boss. Dr. Choi is the new chief resident. Dr. Charles approaches Sarah with an interesting opportunity that catches her off-guard. April faces her recently discovered illness.

Sharon Goodwin's childhood sweetheart arrives at the hospital, but finds himself in dire straits. To help get his financial footing, Dr. Halstead gets lured into a concierge doctor app idea. Meanwhile, a young woman with a heart infection is treated by Dr. Rhodes against Dr. Charles' advice and Reese's former patient, a sex trafficking victim, reaches out to her for help.

It's a long night on the graveyard shift at Chicago Med, especially for Dr. Reese, who must deal with pronouncing patients dead on more than one occasion. April gets called in to work, much to the dismay of Tate, who pressures her to slow down. Meanwhile, Dr. Charles passes along some vital news to Dr. Latham, and Goodwin asks Dr. Rhodes to work on a most unusual patient.

Dr. Manning and Dr. Charles treat a teenage girl with a rapidly changing set of symptoms that has everyone perplexed. Dr. Choi and medical student Jeff Clark encounter a 19 year-old tough guy who is brought into the hospital in severe distress. Once they establish the cause of the pain, the situation quickly turns dangerous and a resolved Dr. Reese does her best to help. Dr. Halstead must deal with a difficult case that is further complicated by Dr. Stohl, who has a camera crew following him around to shoot a promotional video spotlighting the hospital.

Chicago Med braces for an influx of trauma patients when a pre-dawn pileup finds the hospital in full scramble mode. As a result of the storm and emergencies, supplies become limited and Goodwin, Dr. Manning and Dr. Halstead must deal with making an impossible decision. Meanwhile, Dr. Choi handles a severely burned patient who has one final request and Dr. Charles deals with an agitated patient.

It's a miracle when a trauma patient survives the trip to the hospital, putting the pressure on Dr. Rhodes to keep the man alive. Dr. Choi and Dr. Manning have difficulty diagnosing the location of infection in a paralyzed patient. Dr. Reese must find purpose for a grieving widower who relies on a superhero costume. Meanwhile, April pushes Dr. Halstead to use unproved medications to help a patient with no other options.

Dr. Reese is contacted for help by a troubled teen in a psychiatric facility and Dr. Manning tries to help parents make a decision about their comatose daughter's surprise pregnancy. April begins to deal with repercussions from her personal life. Meanwhile, Dr. Choi and Dr. Rhodes work to save both a young girl from Ecuador who collapsed mid-flight, as well as her mother, who made great sacrifices for her daughter.

A suicide shakes the staff. Dr. Choi and Dr. Halstead face off over how to treat a patient with stroke symptoms. Family turmoil unfolds when a boy is treated after falling in a river. The importance of learning from mistakes is emphasized to Dr. Reese.