The new season is moving from college campus to a hospital where some of the most fascinating and bizarre medical cases are under observation, said The Hollywood Reporter.
The 52-year-old "Fuller House" star will play Dr Brock Holt, the hospital's brilliant, but secretive, head surgeon.
Stars returning for new season include Jamie Lee Curtis, Emma Roberts, Lea Michele, Abigail Breslin, Keke Palmer, Glen Powell and Niecy Nash.
Stamos' work on the show will reunite him with creator Ryan Murphy, with whom he worked on "Glee".