Ventimiglia was born in Orange County, California, the son of Carol (née Wilson) and Peter Ventimiglia. His father is Italian of Sicilian descent and his mother has Irish, English, Scottish, French, Cherokee and Blackfoot ancestry. His last name, "Ventimiglia", is the name of a town of Ventimiglia in Liguria, Italy, which later gave its name to another city of Ventimiglia di Sicilia, and means "Twenty Miles". The youngest of three children, he has two older sisters. He was born with dead nerve endings in his lower left lip. When he was younger, Ventimiglia's older sisters dressed him up as Madonna and took photos. He found the photos when he was 13 years old and tore them up.

Ventimiglia attended El Modena High School in Orange, California, where he wrestled and held the office of president in student government (ASB). He graduated in 1995. At eighteen years of age, Ventimiglia received a scholarship to study at the American Conservatory Theater for their summer program. He a