Dr. Douglas "Doogie" Howser (Harris) is the son of David (James Sikking) and Katherine Howser (Belinda Montgomery). As a child, he twice survived early-stage pediatric leukemia, "first when I was four and then...again when I was six", after his father—a family physician—discovered suspicious bruising. The experience fueled Howser's desire to also enter medicine.

Possessing a genius intellect and an eidetic memory, Howser got a perfect score on the SAT at the age of six. He completed high school in nine weeks, graduated from Princeton University at age 10, and finished medical school four years later. At age 14, Howser was the youngest licensed doctor in the country.

The series begins on Howser's 16th birthday; the cold open of the pilot episode shows him stopping his field test for his driver's license to help an injured person at the scene of a traffic accident. Howser is a resident surgeon at Eastman Medical Center in Los Angeles, and still lives at home with his parents. His best friend and neighbor, Vinnie Delpino (Max Casella), is a more typical teenager—climbing through Howser's bedroom window to visit—and keeps him grounded in life outside his profession. Howser keeps a diary on his computer; the episodes typically end with him making an entry in it.