Having survived COVID, Meredith searches for her next big career move and finds it at Mayo Clinic in Minnesota, where David Hamilton persuades her to lead research on a cure for Parkinson's disease at The Grey Center. Meredith recruits Amelia for the project and runs into Nick Marsh. The two rekindle their romance as she splits her time between Seattle and Minnesota. Eventually, she is invited to move to Minnesota to join the Mayo Clinic staff full time, causing friction with her former mentors, who struggle to keep the residency program from being shut down.
Looking to reinvent the teaching of the residents after the COVID year, Richard develops the Webber Method, a teaching method that allows the residents to take charge during non-critical parts of surgeries. When Levi loses a patient on the table while not following the method's rules, the method comes under scrutiny and Richard begins doubting his aptitude as a teacher and surgeon.
Owen illegally dispenses lethal drugs to veterans dying of pulmonary fibrosis while setting up research to properly aid said veterans. Megan Hunt and Farouk visit for Owen and Teddy's wedding as Farouk grows sick, resulting in a heart transplant. A near-death experience causes Owen to come clean about his actions to Cormac, who decides to remove himself from the situation altogether by abruptly relocating back to Ireland with his sons. Teddy learns about Owen's actions as word spreads amongst the veterans, putting a heavy strain on their marriage as he risks being charged with a felony.
Amelia co-parents with Link after his marriage proposal definitively ends their marriage. While working on the research project, she falls for neuroscientist Kai Bartley and the two develop a romantic relationship.
Newlyweds Winston and Maggie spend some time apart while the latter aids her father in Boston after hip surgery. Later, Maggie is faced with a side of Winston she never saw before due to the arrival of Winston's brother Wendell Ndugu.
Levi grows more confident, but his hubris results in the death of a patient. He leaves the residency program and breaks up with Nico. His depressed state causes his mother to start a smear campaign against the residency program, causing a formal investigation into the program.
Link and new mother Jo co-habitate with their children and venture into friends with benefits territory while Jo continues her training as an OB/GYN resident.
Addison Forbes Montgomery visits multiple times to perform and follow up on a uterine transplant.