Isaac and Braeden are brought into the ER, and Melissa asks Isaac why he isn't healing. He deflects the question and tells her to take care of Braeden. Braeden attempts to say that she's looking for Scott, but Melissa doesn't hear it. She checks on Isaac's wound later, which is healing but slowly. Isaac is scheduled for surgery, which is going to cause a problem. She calls Scott because Derek isn't answering. The Sheriff wants to see Braeden, but Melissa tells him that she's sedated. When Scott arrives, Melissa tells him about Isaac and Braeden and sends him to see Isaac.
Melissa calls Stiles in to the hospital to show him the bodies that have been coming in. They've all been strangled, had their throats cut, and heads bashed. This makes it obvious that Cora and Boyd didn't kill them. She then shows him Heather, not knowing that he knew her. The information leads Stiles to realize that they were all virgins.
Melissa is head nurse triaging cases in the ER. Scott brings her dinner because she's too busy to get it herself. There's been a 10 car pile up and the ER attending is not answering. They have a replacement coming in, but she's late. A woman asks Melissa for some painkillers, but she can't give her anything without first being able to check for complications. While they're waiting, Ethan brings Danny in, who is having trouble breathing. Melissa checks him out and determines he has a Tension Pneumothorax. Fearing Danny might die before a doctor can see him, Melissa performs a needle thoracostomy and restores his ability to breathe. Scott and Ethan are impressed. Danny is grateful. When Dr. Hilyard's car appears in the parking lot without her in it, Melissa gives a statement to the Sheriff about their missing doctors. Scott and Isaac spend the night in Melissa's room to protect her from being taken. They fell asleep, although she appreciates the effort.
When they bring in Dr. Hilyard's body, Melissa explains to the Sheriff how these people could be asphyxiated without being strangled. They realize the people are being hung by their wrists until their body weight kills them.
The Sheriff asks Melissa to look up old records on a girl that was brought into the hospital with her face all slashed up. She finds the file and tells him that while the girl was in the hospital, birds kept flying into the walls and windows, killing themselves. The Sheriff was the one who found Julia Baccari.
There's a storm raging, which knocked the power in the hospital out. Melissa is organizing getting everyone transferred. Just as she's got almost everyone, Derek, Scott, Stiles, and Jennifer show up. Melissa tells them that the last ambulance is leaving in 30 minutes so they have to get Cora on it. She goes back to getting everyone else out. She finds Deucalion's cane embedded in the wall next to the elevator, and he eases the cane from her hands. Duke takes her hostage and makes her announce over the PA that Scott has to deliver Jennifer to him. Deucalion lets Melissa go as a gesture of good will toward Scott. She finds the twins fighting Scott in a hallway and hits them with a jolt from the defibrillator. They meet up with Chris, Isaac, and Allison and hatch a plan to save Derek and Jennifer, who are trapped in an elevator. While everyone else acts as a distraction, Melissa goes to the roof to turn the power to the elevator back on. Jennifer then breaks out of the elevator and takes Melissa as a guardian sacrifice. She wakes up tied to a post in the root cellar along with Sheriff Stilinski.
Chris gets captured by Jennifer, and Melissa and the Sheriff greet him. Melissa admits that she's been filling the Sheriff in on a few things. She listens as the Sheriff recalls an encounter he had with a girl who was dying who told him that he should go and see his wife because she was dying, too, but he didn't listen.
Melissa, Chris, and the Sheriff continue to chat while tied up. Chris had a small sonic emitter that he turned on the hopes that a Werewolf would hear it, but so far nothing. Melissa asks if either of them have an itch they can't scratch, and the Sheriff jokes that he does now. Isaac and Allison eventually find them as a storm starts kicking up. They get their ropes off, but the root cellar starts to collapse before they can escape. Isaac holds up a structural beam to keep them all from being crushed. Stiles appears with a metal bat and shoves it under the beam to hold it up.
Scott throws Isaac into the wall for being into Allison, and Melissa yells at them for beating up her house and sends them to school. Later, she finds Scott and his father in the house. Scott tries to throw his dad out for trying to get Sheriff Stillinski fired. Scott's anger starts to take over, and Melissa ushers him aside and advises him to be his own anchor to keep his shifts under control. He's able to pull the transformations back.
Agent McCall is overseeing the transfer of William Barrow to Beacon Hills Hospital. Melissa is the in ER when they come in and breaks up an argument between Agent McCall and Sheriff Stilinski. Melissa is going to have to do the pre-op interview. She asks Barrow standard questions and opens up his shirt to check his heart. He's covered in scars. She asks him why he did it, and he tells her that the kids he killed had glowing eyes. When Barrow starts to rant, Melissa runs away. She is in the OR when they open Barrow up and sees what appears to be a tumor inside him pulsing. It bursts, releasing flies. Barrow makes his escape, but Melissa is okay. She tells the Sheriff what Barrow said about kids with glowing eyes. The Sheriff heads to the school, which is close to where Barrow abandoned the ambulance he stole. Melissa then brings some of his clothes to Scott so the Werewolf can look for him. That evening she gets a call from Scott asking why she didn't change her name back to Delgado after her divorce, and she tells him that she wanted the two of them to have the same last name.
Stiles walks into the ER upset and nearly in tears. Melissa takes him into a room and records his symptoms. She asks how much sleep he's getting and decides that many of his symptoms are due to sleep deprivation. She gives him a sedative and puts him to bed. She brushes his hair, and he calls her mom. When she checks his chart later, she's reminded of Stiles's mother's symtoms and goes to check her chart. They all match up. She heads home to find Agent McCall, Scott, and Kira there. The Oni show up and attack, and Derek enters the house to help. The twins bust in through the window. As soon as they have the Oni outside the house, Melissa smashes a jar of mountain ash across the threshold of the door to seal the house. Melissa then starts treating Agent McCall's stab wound. They have to get him to a hospital before he bleeds out. They could call the Sheriff, but that might get more people hurt, so they don't. Rafael says he needs to stalk to Scott, but Melissa makes him wait. After the Oni leave, they rush Rafael to the ER.
The Sheriff comes to the hospital because Stiles is missing and they found his Jeep in the parking lot. Melissa has people searching but they haven't found anything yet. She takes him to the basement to look there. After work, she goes to the sheriff station and offers to help Agent McCall look for Stiles. They start driving and Agent McCall reveals that he thinks Stiles is still asleep. They joke about a time Rafael was so drunk he peed in the closet. His point is that Stiles might only think he's in a basement. He thinks he knows where he really is based on something Stiles said about it smelling really bad. They find him in Malia's old den and bring him to the hospital. Everyone waits to hear if Stiles is okay, and then Melissa sends Scott and Lydia home. The next day she tries to broach the subject of Stiles's symptoms with the Sheriff, but he's already made the connection. He agrees to give Stiles an MRI. Melissa stands next to him while they watch Stiles get the scan. They look on as the results show up on the screen showing brain atrophy.
It's been two days since the nogitsune took over Stiles and disappeared from the hospital. Melissa suggests she and Scott stop at the hospital to see Isaac before school. They find Allison sleeping outside his room. Melissa opens the door to the isolation room and urges them to hurry up.
After Aiden and Lydia find Stiles in the parking lot, they bring him to Scott's house. Melissa thinks it's crazy that they aren't taking him to a hospital, but it's the nogitsune instead of Stiles. Deaton immobilizes him with kanima venom and they tape his mouth shut. Melissa tries to call the Sheriff to tell him they found Stiles but he's busy. She starts tending to the nogitsune's wound, and he looks at her with tears in his eyes. She asks if it's him and take the tape off his mouth, but the nogitsune laughs at her for being so easily manipulated. He taunts her with the secret that Agent McCall has been keeping from Scott and says that Scott will hate her. She puts the tape back on his mouth. She's there to witness the nogitsune vomiting up the bandages that become Stiles.
Melissa checks Stiles's vitals and can't find anything wrong with him. She doesn't like his plan to have himself tested by the Oni but doesn't stop him.
Melissa and Agent McCall discuss Rafael just going back to San Francisco without saying good-bye to Scott. Melissa can't imagine a worse plan. She tells him that he can't leave after one fight if he really wants to have a relationship with Scott. They get in the elevator, and when the door opens they see Oni massacring people. One of them slices Melissa on the leg before they can close the doors again. She gets weak from blood loss and makes Rafael promise to try to work things out with Scott. When the elevator door opens again the Oni are gone, and Rafael brings Melissa out to find someone to help her.
After the nogitsune is defeated, Melissa finds Scott at the dining room table crying and hugs him.