The stories of the men and women who work the overnight shift at San Antonio Memorial Hospital. They are an irreverent and special breed, particularly adrenaline junkie T.C. Callahan.
Jordan and Drew perform a daring rescue by jumping from a chopper. Landing at the nearest VA hospital, Jordan sparks a plan to appease Julian and reunite her night shift team. Back at the hospital, Paul deals with the repercussions of standing up to his father while Scott dives headlong into his professional life. Kenny butts heads with Cain, a traveling nurse with a mysterious past. Shannon indoctrinates Cain as they work in San Antonio Memorial's understaffed and overworked ER. Meanwhile, TC is held captive in Syria. In order to find Syd, TC must treat his captor instead of returning to the safety of an air base with a civilian volunteer, Amira.
After performing a daring on-site rescue to save a teenage girl, Drew is forced to re-evaluate his priorities as a new father. Back at the hospital, the ER is flooded with mass casualty victims from an amusement park disaster. Hoping to get Paul back on staff, Jordan facilitates a rapprochement between Paul and his father. Meanwhile, Scott pursues a more active role in the hospital and Kenny tries to put Cain in his place.
Jordan and Cain figure out their professional dynamic as they work on a patient with extreme injuries from an oil field explosion. Drew and Paul receive a patient from the same accident, and must figure out a solution to save the patient's severed hand. Scott is caught off guard when Annie shows up to the hospital with an unexpected guest from his past. Kenny and Shannon struggle to adjust to their new living situation. Meanwhile, TC and Amira clash over treating a Syrian child on the American base.
When a patient from a distant town journeys to SAM for surgery, Scott commits to helping her against all odds. Jordan and Cain help a wounded veteran come to terms with a diagnosis he doesn't believe he has. Meanwhile, Drew struggles with the exhaustion of being a working parent and finds support from an unusual patient. After a long night, Kenny learns life is too short to worry about trivial matters. TC joins a daring rescue mission in Syria.
Drew, his mom, and Rick's flight home turns into a medical crisis at 35,000 feet when passengers become sickened one by one. Jordan, Paul, Shannon, Kenny, and Cain spend their day off at an obstacle course fundraiser for Cystic Fibrosis, hosted by Akbar Gbajabjamila. Scott finds himself on a Tinder date he won't soon forget. Meanwhile, TC puts his own life in danger to operate on a soldier.
Kenny joins Drew at his MMA veteran's support group and finds himself in the fight of his life. Jordan and Cain treat casualties from a hotel fire while Shannon follows a hunch to help save a young victim. Paul's superstar sister, Dr. Bella Cummings, pays a visit to San Antonio Memorial. Meanwhile, TC finally returns home, forcing him to deal with Topher's death.
When protestors descend on a funeral for a dear member of the night shift family, multiple veterans are injured and brought to San Antonio Memorial for treatment. A high profile politician from Drew's past triggers flashbacks to his time in Iraq. Jordan, Scott, and TC disagree on how to best provide care for the politician. Paul and Shannon must improvise while tending to Doug, a former POW. Cain and Drew treat a fearless photographer.
When Jordan realizes the hospital is under cyber-attack, she leads the team in managing patient care as chaos ensues. Drew and Kenny treat a critical patient forcing Drew to call on his medical and military training. TC joins Rick and his partner on a SWAT drug raid. Meanwhile, he wrestles with whether or not he should return to Syria to tie up loose ends.
TC and Jordan accompany a SWAT team on a raid and wind up with an emergency room full of sickened immigrants, including one with murderous intentions. Scott pulls a dream team together to impress the Colonel in charge of setting up a combat training program. More is learned about Cain's past. Kenny shares some big news with the group, while Shannon keeps something personal from Paul.
A shooting at a nearby college sends TC, Jordan, Drew and Amira into the field, where they assist Rick with a deadly situation. Scott implements a new training program and locks horns with Julian. Drew struggles with frustrations about going to Army Ranger School while Shannon and TC both contemplate their future at San Antonio Memorial.