A gifted but cantankerous diagnostician, Dr. Gregory House, leads a team of skilled and diverse doctors at Princeton-Plainsboro Teaching Hospital. Known for his unconventional thinking and lack of bedside manner, House excels in solving complex medical mysteries that baffle others. While lacking social graces, he's unmatched in his field due to his keen intellect and unorthodox methods, often risking his career by breaking rules to get to the truth. Constantly in pain from a significant physical ailment, House struggles with addiction to pain medication, which further complicates his interactions with patients and colleagues. Driven by an insatiable curiosity, House relies heavily on logical deductions, mirroring a detective-like approach to medicine.

Throughout the series, House's relationships with his team, friends, and superiors evolve. His closest ally is Dr. James Wilson, the head of oncology, who provides him with friendship and counsel despite House's abrasive behavior. The hospital administration, particularly Dr. Lisa Cuddy, often finds itself at odds with House's methods but recognizes his brilliance. A central dynamic involves House's teaching and testing of his fellows—doctors eager to learn but frequently tested by House's challenging, and sometimes ethically dubious, methods. This interplay drives each episode to a climax of revelation or moral quandary. As new characters join and others depart, House's influence remains constant as he confronts both external medical cases and his internal personal battles.