After a harrowing hostage incident shakes up the night shift crew, psychologist Landry de la Cruz is stunned to learn that her patient Dr. TC Callahan is in a relationship with another surgeon, whom she is hiding from Jordan. The team must also contend with a new boss, Michael Ragosa, who has his eye on cutting costs and doesn't believe in bringing in replacements for experienced staffers. Among the late-night doctors and residents are Topher, an ex-Army doctor who wears flip flops and works to the beat of his own drum; Drew, a sexy exotic dancer with serious ER issues; and Krista, an ambitious young resident and squeamish former swimmer who can't stop chasing her dreams.

Weeks after a PTSD breakdown, TC is haunted by the death of a close friend in combat. Then, a man who survived a bullet to the head arrives in the ER with a failing heart. TC believes he can convince the family of a brain-dead drug addict to donate their loved one's heart directly to Nick. Meanwhile, prompted by Landry, Topher opens up about his personal life.

A menacing cop infiltrates the ER and takes hostages. The gang, along with Dr. Joey Chavez, must rescue the lone survivor from a small plane crash in the nearby mountains. Then, a female college student collapses and is diagnosed with Toxic Shock Syndrome. She had a tampon in her vagina, which Paul finds. Tests reveal semen on the tampon, leading the doc to suspect a frat party is behind her illness.