After a harrowing hostage incident left the night shift team badly shaken, everyone is finally back to business... everyone except TC Callahan, who has been temporarily suspended from the hospital after a PTSD breakdown on the job. After recovering from his near-fatal gunshot wound, Topher Zia has temporarily taken over as chief of the night shift while Jordan Alexander fields scrutiny over her medical mishandling of the man who shot him. TC can't stay away from the action however and joins Jordan out in the field, and with the help of head surgeon Scott Clemmens, they push the limits of medical technology to save a father trapped beneath an elevator. Dr. Joey Chavez brings a new zen vibe to the ER when he steps in as chief surgeon on a freak motorcycle accident case, working to the beat of his own drum. Meanwhile, Ragosa returns to the ER with a surprising new lease on life after surviving cancer.
When a rancher accidentally shoots his own wife, TC, Kenny and Paul try desperately to save her but it's too late. Before TC can come to terms with the loss of his patient, he's sent out to the scene of a crazy teenage ranch party where he performs a risky surgery in order to save the life of a young football star. Back at the hospital, Jordan and Kenny rush to the aid of a beauty queen who has wandered into the emergency room in severe distress but treating her symptoms only leads to further complications. Topher decides he wants to keep the top job and builds the nerve to approach Jordan about it.
The night shift crew is put to the test when a teenage couple and a young mom land in the emergency room after a serious car crash. Topher, TC, Jordan and Scott tend to the youngsters, who were returning from their secret wedding. As the girl's condition worsens, TC tries in vein to calm her distraught father. Jordan and Gwen tend to the other victim, a young pregnant woman whose fiancé is deployed in Afghanistan. The team hastily arranges a proxy wedding so that she can be married before delivering the baby through an emergency caesarian section. Meanwhile, Paul tends to a wealthy, eccentric hospital benefactor who teaches him it's ok to follow his heart.
TC, Joey, and Gwen rescue an injured skydiver from the site of a near-fatal crash. Joey and Krista counsel the skydiver's girlfriend after they uncover serious complications in the operating room. TC, Topher, and Ragosa treat an electrocuted janitor whose family gathers around him in the ER. When the patient's wife and children suddenly come down with their own life-threatening symptoms, the night shift team works overtime to save them. Jordan and Paul attend to a college student who comes to the ER with a mild fever. As they uncover the cause of her condition, Jordan teaches Paul a difficult lesson about his limitations as a doctor. Meanwhile, Rick arrives at the hospital with an injury that he hides from his boyfriend, Drew.
A patient's exposure to radiation sends the Night Shift into chaos. Topher implements an immediate quarantine and locks down the ER. Paul cares for the quarantined patient with the help of Ragosa and Kenny. Meanwhile, TC, Drew, and Gwen race to the site of a multi-victim car cash, where they discover an injured police officer at the heart of the accident. Back at the hospital TC and Jordan work desperately to save the officer's life using an unconventional procedure. TC gets an unwelcome surprise when his troubled sister-in-law Annie shows up out of the blue. Still adrift and grieving over the death of her husband, Annie is eager to reminisce with TC about the good old days. Meanwhile, a former patient harasses Jordan, and Drew struggles with his recent breakup. Joey pushes Krista to take her future into her own hands.
As a thick fog descends upon San Antonio, the doctors must improvise to save the victims of a car crash; Topher, Drew and Kenny treat siblings injured in the fog.
T.C. discovers his sister-in-law's complicated history after he treats her for a fall down stairs; Jordan and Gwen tend to a boy who fell down a well; Ragosa must come clean to his daughter about his position at the hospital.
A gas explosion sees dozens of casualties being sent to San Antonio Memorial Hospital.
Drew finds himself in the middle of a shooting at a friend's Army promotion ceremony and springs into action, disarming the shooter. Later, he has to treat his best friend's wife and finds that her bullet injury has revealed an even more severe medical condition. Topher and TC treat a young woman whose chronic bouts of psychosis are becoming a danger to herself and her family. The ER team has to scramble to diagnose and treat the young woman before she is arrested for her mysterious, unhappy behavior. Paul treats a nine-year-old boy with severe cystic fibrosis and his concern for the boy's health leads him to break a few rules regarding hospital protocol. Meanwhile, Ragosa is devastated when his financial troubles put his daughter's Quinceañera in jeopardy.
Jordan and Krista rescue the victim of a motorcycle crash on a deserted rural road. Miles away from an ER, they improvise emergency medical care for the injured motorcyclist and rush him to the nearest operating room - in a veterinary hospital. Back at the hospital, TC and Paul race to diagnose the cause of a teenager's life-threatening overeating condition while Topher treats a friend who is concealing a dangerous secret. Meanwhile, Drew shrinks from the media's eye as his heroic gunman takedown goes viral, but he gets a welcome surprise when Rick returns.
A building collapses during a rodeo; a severely injured cowboy exhibits strange symptoms; Scott causes a serious car accident.
TC introduces the night shift team to his MMA group therapy leader Colonel Elwood "Smalls" Green, who surprises the group with special greeting from the White House. Jordan and Paul help a nine-year-old boy with a serious fever. When his high-strung mother begins to exhibit signs of distress as well, the team realizes there is more to the family dynamic than meets the eye. Topher is faced with a big decision about making an emergency trip overseas to help an old mentor. TC grapples with whether to accompany him on the journey. Meanwhile, Ragosa, Drew and Krista compete for the strangest cases of the night as the full moon brings out the worst in people.
Drew and Paul head to the scene of a multi-car collision while the newly-anointed Dr. Ragosa along with Jordan, Scott, Krista and Kenny, manage the deluge of incoming victims. Meanwhile, TC and Topher head into a war zone to treat an old friend.
TC and Topher return from Afghanistan to find Jordan's life on the line and San Antonio under fire as two deadly snipers terrorize the city. TC and Scott unite to care for a comatose Jordan and her unborn baby. Drew and Gwen are caught in a fire fight when a SWAT Team corners the two snipers. Meanwhile Dr. Joey Chavez scrubs back in for the night, and he calls into question his future with Krista. Ragosa helps Paul make a difficult decision about his future.