De Palma was born on September 11, 1940, in Newark, New Jersey, the youngest of three boys. His Italian-American parents were Vivienne DePalma (née Muti), and Anthony F. DePalma, an orthopedic surgeon who was the son of immigrants from Alberona, Province of Foggia. He was raised in Philadelphia, Pennsylvania and New Hampshire, and attended various Protestant and Quaker schools, eventually graduating from Friends' Central School. He had a poor relationship with his father, and would secretly follow him to record his adulterous behavior; this would eventually inspire the teenage character in De Palma's Dressed to Kill (1980). When he was in high school, he built computers. He won a regional science-fair prize for his project "An Analog Computer to Solve Differential Equations".
Enrolled at Columbia University as a physics student, De Palma became enraptured with filmmaking after seeing Orson Welles' Citizen Kane (1941) and Alfred Hitchcock's Vertigo (1958). After receiving his undergraduate degree in 1962, De Palma enrolled at the newly coed Sarah Lawrence College as a graduate student in their theater department, earning an M.A. in the discipline in 1964 as one of the first male students in a predominantly female school. Once there, influences as various as drama teacher Wilford Leach, the Maysles brothers, Michelangelo Antonioni, Andy Warhol and Jean-Luc Godard, impressed upon De Palma the many styles and themes that would shape his work in the coming decades.