The emergency department's grand opening is interrupted by an onslaught of crash victims, pushing hospital administrator Sharon Goodwin (S. Epatha Merkerson) 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 (Colin Donnell), pregnant pediatrics specialist Dr. Natalie Manning (Torrey DeVitto), third-year resident Dr. Will Halstead (Nick Gehlfuss), military-trained Dr. Ethan Choi (Brian Tee), nurse April Sexton (Yaya Dacosta) and head of psychiatry Dr. Daniel Charles (Oliver Platt) must pull together to save lives. Rounding out the team is medical student Sarah Reese (Rachel DiPillo), who quickly learns some of the hard lessons that come with life in the Emergency Department.

As Dr. Ethan Choi (Brian Tee) 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 (Torrey DeVitto) and hospital administrator Sharon Goodwin (S. Epatha Merkerson) as they're forced to make some difficult decisions about the teen's future. Dr. Will Halstead (Nick Gehlfuss) treats a hypochondriac with chest pains while struggling to navigate his overbearing wife. Meanwhile, med student Sarah Reese (Rachel DiPillo) and psychiatrist Dr. Daniel Charles (Oliver Platt) treat a patient suffering from dementia, only to discover she may not have dementia at all.

When Dr. Connor Rhodes (Colin Donnell) takes the case of a close family friend who's been impaled by glass shards, he's reunited with his sister, Claire Rhodes (guest start Christina Brucato), and forced to confront his past. Meanwhile, Dr. Natalie Manning (Torrey DeVitto) 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 (S. Epatha Merkerson) attempts to keep the press at bay. To treat a teenager with an eating disorder, Dr. Natalie Manning (Torrey DeVitto) enlists the help of Dr. Daniel Charles (Oliver Platt), but his unorthodox methods rub Natalie and the teenage girl's mother the wrong way. Meanwhile, Nurse April Sexton (Yaya DaCosta), Dr. Will Halstead (Nick Gehlfuss) and Dr. Ethan Choi (Brian Tee) treat a racist patient whose strange form of bigotry surprises them all.

A member of the Firehouse family clings to life and members of the Chicago Med staff discover a highly unusual parallel between cases - a three-part story arc crosses over into "Chicago Fire" and concludes the following night on "Chicago P.D. 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 (Colin Donnell) and Dr. Toni Zanetti (guest star Julie Berman) 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 (Torrey DeVitto) makes preparations for her pregnancy and Nurse April Sexton's (Yaya DaCosta) brother (guest star Roland Buck III) 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 (S. Epatha Merkerson) to receive a visit from the Department of Homeland Security regarding the undocumented immigrants. Cornelius Rhodes (guest star DW Moffett), the wealthy father of Dr. Connor Rhodes (Colin Donnell), 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 (Torrey De Vitto) big day arrives and Dr. Will Halstead's (Nick Gehlfuss) good intentions to help are misconstrued by her mother-in-law, Helen (guest star Annie Potts). Meanwhile, Dr. Sarah Reese (Rachel DiPillo) asks Dr. Charles (Oliver Platt) 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.