The 15th and final season of ER begins with the devastating repercussions of the ambulance explosion. As Morris and Neela do everything they can to save a wounded colleague, Abby treats a young girl injured during the blast.

Everyone in the ER is trying to cope with the loss of their colleague. The staff feels defensive toward the new Chief and her tough disposition. Gates and the new interns treat a bio terrorist who has a lethal secret that endangers them all. Neela makes a great effort to get Dubenko back on the surgery staff, and gets help from an unexpected source.

Abby's first day as an attending is bittersweet. Neela is hurt when she finds out Abby's news from someone else. Abby and the new ER Chief argue over how to treat a gunshot victim. Abby comes to Sam's aid when she faces a nurses' disciplinary board.

Dr. Banfield defends herself during a mugging. Dubenko returns to work, due in no small part to Brenner's organized protests. A young gymnast comes into the ER with injuries consistent with a fall, but Banfield and Gates each think a different family member may actually be to blame. Sarah neglects to ask Gates's permission before getting her tongue pierced.

It's Halloween night, and the interns continue to be paired with the residents. Gates's teaching methods with Daria, and her responses, belittle Sam. A school fight results in a stabbing and a nose that won't stop bleeding, with Brenner treating the victims and being deeply affected by the truth behind their confrontation. The staff, especially Neela, are enthusiastic about a surprise visitor. Gates gets locked in a maintenance area with a quiet young boy.

Chaz, now a med student, begins his ER rotation. Morris takes him under his wing and shows him some risky procedures, endangering a patient and raising Banfield's ire. Neela becomes upset when Banfield questions her authority and skills in front of her intern. Gates invites Sam and Alex to move in with him and Sarah.

While out for a mind-clearing run, Banfield encounters a desperate situation and finds herself trying to rescue a young girl from drowning in a nearby lake. Painful memories of her son in mortal danger and Dr. Greene's heroic attempts to save him are triggered during the experience. Meanwhile, Gates attempts to pull some strings to help out a homeless war veteran, and the interns continue to struggle in the ER.

Sam gets frustrated with Gates when he gets obsessed with finding a homeless war hero. Neela is upset at her intern after he gets the entire surgery department into a lawsuit. A husband and wife come into the ER after someone tried to burn down their home. Brenner loses his cool with a patient and it gets physical.

As a snowstorm hits Chicago, Sam's son Alex crashes a car and ends up in critical condition in the ER. Neela gives a deposition in the malpractice suit against her. Banfield and Morris are both at a medical conference in Omaha, and when the snow cancels all flights out, they share a memorable and surprising evening.

A package for Morris from his deceased father is delivered to the ER. Sam has some anxiety over Alex being removed from the ventilator. A woman with a high-risk pregnancy worries that she will be deported. An old friend returns to celebrate the holidays.

When a drug deal goes bad, two brothers sustain serious injuries and are brought to the ER. Tensions continue between Gates and Sam, coming to a head when Tony is the last to know Alex is about to be released from the hospital. Neela has to tell a young girl with sickle cell anemia that she must have an operation, and the case leads her to consider specializing in pediatric surgery. A feisty patient takes Morris into her confidence. Banfield ponders her choices about expanding her family.

Neela has recurring dreams about trying to save a girl with sickle cell anemia. In them, she also goes to an attending interview and sees an old colleague, has conversations with Ray, welcomes Brenner back from Australia, and assists Gates and Banfield in trying to save a "dream runner" who jumped out of a window during his sleep.

Morris faces a complicated case involving a young girl hit while riding her bicycle. Gates finds it very difficult to let go of his feelings for Sam. Neela becomes quite flustered when Brenner returns from Australia.

Gates and Morris tend to an elderly man who was assaulted on the street. Sam 's sister shows up unexpectedly. Brenner and Dubenko clash while treating a mother thought to have late-stage cancer. Dr. Morgenstern returns to the ER to assist a former mentor who is seriously ill.

A car accident in the ambulance bay injures a woman with a young child and leaves the mother in need of surgery with a significant recovery time. Brenner has difficulty finding a family member to care for the daughter. Gates treats an elderly patient who refuses treatment because he's afraid his condition will prolong an inevitable death. Morris impresses Claudia and her family. Neela tells Brenner about her job offer from North Carolina.

It's Valentine's Day. Dr. John Carter is back at the County. Brenner and Neela are getting closer. Dr. Banfield is having a hard time trying to have a baby. And Puck and mushrooms may not be a good combination.

Carter finds himself struggling with County's new technology and procedures. After becoming frustrated with the in vitro-fertilization, Banfield and her husband discuss adoption as an option. Sam's mother arrives in an altered state of mind.

A camera crew shooting footage for a documentary interviews members of the ER staff. Detective Claudia Diaz is brought in, critically injured with gunshot wounds. Neela laments the lack of communication between her and Brenner. Sam struggles to reconcile with her mother. Carter's condition worsens quite suddenly.

Neela and Sam are shocked when they arrive back to the airport with transplant organs only to find that their plane has left them. Dr. Carter gets a surprise visit from an old friend while waiting for his kidney transplant. Dr. Banfield bonds with an abandoned baby boy that is left at the ER.

On Neela's last day at County, she has doubts as to whether she is making the right decision.

The ER doctors and nurses help out at Camp Del Corazon, a camp for kids who have had open-heart surgery, working alongside the camp counselor.

As Carter prepares to open a new facility for the underprivileged, some old friends/colleagues gather. Rachel Greene, Mark Greene's daughter, applies for an internship at County.