De Palma is often cited as a leading member of the Movie Brat generation of film directors, a distinct pedigree who either emerged from film schools or are overtly cine-literate. His contemporaries include Paul Schrader, Martin Scorsese, John Milius, George Lucas, Francis Ford Coppola, and Steven Spielberg. Throughout the 1970s and early 1980s, De Palma worked repeatedly with actors Jennifer Salt, Amy Irving, Nancy Allen (his wife from 1979 to 1983), William Finley, Charles Durning, Gerrit Graham, cinematographers Stephen H. Burum and Vilmos Zsigmond, set designer Jack Fisk, and composers Bernard Herrmann and Pino Donaggio. De Palma is credited with fostering the careers of or outright discovering Robert De Niro, Jill Clayburgh, John C. Reilly, John Leguizamo, and Margot Kidder. De Palma has encouraged and fostered the filmmaking careers of directors such as Mark Romanek and Keith Gordon. Terrence Malick credits seeing De Palma's early films on college campus tours as a validation of independent film, and subsequently switched his attention from philosophy to filmmaking.

De Palma, whose background is Italian Catholic, was raised in Philadelphia and New Jersey in various Protestant and Quaker schools. The frisson between the Catholic and Protestant ethic is exemplified in De Palma's cinema, where the grand guignol exists alongside the status quo, where the normal is made epic and the extraordinary deflated into the mainstream.

Enrolled at Columbia as a physics student, De Palma became enraptured with the filmmaking process after viewing Citizen Kane and Vertigo. He switched majors and enrolled at the newly coed Sarah Lawrence College in the late 1960s, becoming one of the first male students among a female population. Once there, influences as various as drama teacher Wilford Leach, the Maysles brothers, Michelangelo Antonioni, Jean-Luc Godard, Andy Warhol and Alfred Hitchcock impressed upon De Palma the many styles and themes that would shape his own cinema in the coming decades. An early association with discovery Robert De Niro resulted in The Wedding Party, codirected with Leach and producer Cynthia Munroe. The film was shot in 1963 but remained unreleased until 1969, when De Palma's star had risen sufficiently within the Greenwich Village filmmaking scene, though De Niro's remained low enough for the credits to display his name as "Robert Denero". Various small films for the NAACP and The Treasury Department followed.