Years after the murderous events at Kappa House, Dean Munsch purchases an abandoned hospital under the guise of fixing the healthcare system in America. After recruiting surgeons, Dr. Brock Holt and Dr. Cassidy Cascade, as well as medical student Zayday Williams, the Dean shocks everyone when she enlists the services of the disgraced Chanels to join the ranks at the teaching hospital. Meanwhile, secrets from the hospital’s past begin to reveal themselves and a new killer surfaces.
A new patient with a hideous ailment visits the hospital in hope of a cure, but finds a love interest instead. Meanwhile, Chad returns to win Chanel back and, in the process, discovers a dark secret of Brock’s. Then, after another run-in with the killer, Munsch enlists the help of new Quantico special agent Denise Hemphill.
Determined to find out who the killer is, Dean Munsch, Denise and the Chanels question Hester, as well as the sole survivor (guest star Alec Mapa) of the Halloween massacre. Chad accuses Brock of being the killer and makes a shocking proposal to Chanel. Meanwhile, a new patient with an outrageous disorder (guest star Cheri Oteri) leads Chanel #3 and Cassidy to grow closer, and another victim crashes a celebration.
After the latest attack by The Green Meanie leaves everyone shocked and saddened, Dean Munsch and Denise, along with Hester, devise a plan to catch the killer by throwing a Halloween party in the hospital. Meanwhile, Chanel celebrates a different kind of Chanel-O-Ween and attempts to make contact with the killer’s latest victim from beyond the grave. Once the party begins, an outbreak surprises the hospital, leading Brock and Cassidy to jump into action, and another victim falls.
The frightful events of Halloween force Dean Munsch to notify authorities of murders at the Institute, which leads to a surprising influx of new patients. Meanwhile,Chanel is tired of doing dirty work, so she concocts a plan that entails recruiting new patients to join the Chanels. Later, Zayday and Chanel #5 visit a person with ties to the hospital's past; and a new patient's problems have the staff going a bit mad.
After an influx of patents at the C.U.R.E. institute, Dean Munsch and Chanel organize a blood drive to solve the hospital's severe shortage. Meanwhile, Nurse Hoffel sets a plan of revenge in motion, Hester finds a way to join the hospital's staff and a shocking revelation involving The Green Meanie occurs.
In an effort to secure positive press for the hospital, Dean Munsch pitches a risky surgery to Dr. Holt, whose hand begins expressing more of a wild and dangerous personality than ever before. Meanwhile, Chanel #3 forces Cassidy to undergo a psych test to find the root of his condition with surprising results, and Nurse Hoffel sets a devious plan in motion.
A man from Dean Munsch's past checks in to the C.U.R.E. institute with plans to win her back, causing a jealous Brock to further question his relationship with Chanel. Meanwhile, Zayday and Chamberlain devise a plan to discover the origins of The Green Meanie killer with shocking results.
The Chanels are overwhelmed when their TV idol, Dr. Scarlett Lovin, visits the C.U.R.E. Institute. Meanwhile, Hester calls a Green Meanie summit as the killer(s) put their final kill plan into effect.