The emergency department's grand opening is interrupted by an onslaught of crash victims, pushing hospital administrator Sharon Goodwin and her staff to their limits as they frantically work to triage and treat patients. It's all hands on deck as newly hired trauma surgeon Dr. Connor Rhodes, pregnant pediatrics specialist Dr. Natalie Manning, third-year resident Dr. Will Halstead, military-trained Dr. Ethan Choi, nurse April Sexton and head of psychiatry Dr. Daniel Charles must pull together to save lives. Rounding out the team is medical student Sarah Reese, who quickly learns some of the hard lessons that come with life in the Emergency Department.
As Dr. Ethan Choi treats a bleeding teenage girl, he discovers she's just given birth, sparking a frantic search for her abandoned baby. When the details of the teen's troubled past emerge, Ethan finds himself at odds with pediatrician Dr. Natalie Manning and hospital administrator Sharon Goodwin as they're forced to make some difficult decisions about the teen's future. Dr. Will Halstead treats a hypochondriac with chest pains while struggling to navigate his overbearing wife. Meanwhile, med student Sarah Reese and psychiatrist Dr. Daniel Charles treat a patient suffering from dementia, only to discover she may not have dementia at all.
When Dr. Connor Rhodes takes the case of a close family friend who's been impaled by glass shards, he's reunited with his sister, Claire Rhodes, and forced to confront his past. Meanwhile, Dr. Natalie Manning convinces a young musician to undergo a surgery that will save her life but could destroy her hearing.
After shots ring out at a movie theater, the Chicago Med doctors work to treat the victims while hospital administrator Sharon Goodwin attempts to keep the press at bay. To treat a teenager with an eating disorder, Dr. Natalie Manning enlists the help of Dr. Daniel Charles, but his unorthodox methods rub Natalie and the teenage girl's mother the wrong way. Meanwhile, Nurse April Sexton, Dr. Will Halstead and Dr. Ethan Choi treat a racist patient whose strange form of bigotry surprises them all.
Following a knife attack, a member of the team lies in peril and their condition takes a sudden turn for the worse, leaving Dr. Connor Rhodes and Dr. Toni Zanetti scrambling to race against the clock. Word quickly spreads that some of Connor's fellow doctors feel he should have operated sooner, causing tension at the hospital. Dr. Natalie Manning makes preparations for her pregnancy and Nurse April Sexton's brother struggles through his first day at the hospital. Meanwhile, members of the Chicago P.D. Intelligence Unit help investigate whether the case of a women clinging to life after Firehouse 51 pulled her out of a burning building is attempted suicide or murder. As the investigation deepens, a surprising parallel to other patients surfaces.
Two airplane stowaways are brought into the hospital after suffering major injuries from the travel, prompting Sharon Goodwin to receive a visit from the Department of Homeland Security regarding the undocumented immigrants. Cornelius Rhodes, the wealthy father of Dr. Connor Rhodes, is honored after making a big donation to the hospital for a new psych ward, forcing dark family secrets to the surface. Dr. Natalie Manning's big day arrives and Dr. Will Halstead's good intentions to help are misconstrued by her mother-in-law, Helen. Meanwhile, Dr. Sarah Reese asks Dr. Charles for advice on how to deliver heartbreaking news to a young boy while also warning his family about the possibility that their other son may also have the same life-threatening disease.
When legal issues complicate matters that stall a life-saving bone marrow transplant, Sharon Goodwin must decide whether to disobey direct orders or stand by and put a patient's life in jeopardy. April tends to a caring, homeless man who Dr. Charles evaluates, only to come to an unusual diagnosis that explains his recent behavior. Dr. Natalie Manning's parents come to town to see their new grandchild, much to the dismay of her mother-in-law, Helen. Dr. Connor Rhodes treats a couple who are injured on their first date by a hit-and-run driver, who Dr. Halstead discovers has his own reasons for causing the accident.
Dr. Manning returns from maternity leave and helps treat a teen with a long history of medical issues. Dr. Choi attends to a former Navy shipmate with a potentially life-threatening ailment and goes above and beyond the scope of his duties to ensure he gets the proper treatment. Saudi Prince Faisal arrives at the hospital for a planned surgical procedure, but only from Dr. David Downey, the hot-shot surgeon who takes a shine to the work of Dr. Rhodes. Meanwhile, a budding romance between Sarah and hospital lab tech Joey looks hopeful, but April might think otherwise.
Dr. Halstead revives a "do-not-resuscitate" terminally ill cancer patient, and the repercussions prompt his quick removal from the case and a pending lawsuit against Chicago Med. A homeless man's arrival is passed down to April and an uneager Dr. Reese, but the circumstances surrounding his short stay catch both off-guard. Following the assessment and treatment of a bi-polar patient with an unhealthy dependence for lithium, Dr. Choi's own personal issues come to the surface, prompting him to seek the advice of Dr. Charles. The medical staff is shocked to learn one of their own has a life-threatening disease.
Dr. Rhodes and Dr. Downey make plans to operate on Ray, a 9/11 hero who is suffering from pulmonary fibrosis. A new set of lungs could save his life through an innovative surgical procedure but an unforeseen medical problem arises with Ray that might derail the doctor's grand plans. Sarah contemplates which hospital to select for her residency match while Maggie and April make their push for her to remain at Chicago Med. Meanwhile, Dr. Choi works to determine the cause of an injured teenage star hockey player with an overbearing father while Dr. Halstead and Dr. Manning continue to clash.